Substituted pyridines and uses thereof

ABSTRACT

Substituted pyridines that modulate HIF-2a activity, pharmaceutical compositions containing the substituted pyridines, and methods of using these chemical entities for treating proliferative diseases and conditions associated with HIF-2a activity are described herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/131,789, filed on Mar. 11, 2015, and U.S. Provisional Application No.62/219,044, filed on Sep. 15, 2015, each incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

This invention was in part funded by a grant from Cancer PreventionResearch Institute of Texas (Grant number R1009).

An adequate supply of oxygen to tissues is essential in maintainingmammalian cell function and physiology. A deficiency in oxygen supply totissues is a characteristic of a number of pathophysiologic conditionsin which there is insufficient blood flow to provide adequateoxygenation, for example, ischemic disorders, cancer, andatherosclerosis. The hypoxic (low oxygen) environment of tissuesactivates a signaling cascade that drives the induction or repression ofthe transcription of a multitude of genes implicated in events such asangiogenesis (neo-vascularization), glucose metabolism, and cellsurvival/death. A key to this hypoxic transcriptional response lies inthe transcription factor, the hypoxia-inducible factors (HIF). HIFs areoverexpressed in a vast array of cancers through hypoxia-dependent andindependent mechanisms and expression is associated with poor patientprognosis.

HIFs consist of an oxygen-sensitive HIFα subunit and constitutivelyexpressed HIFβ subunit. When HIFs are activated, the HIFα and HIFβsubunits assemble a functional heterodimer (the α subunitheterodimerizes with the β subunit). Both HIFα and HIFβ have twoidentical structural characteristics, a basic helix-loop-helix (bHLH)and PAS domains (PAS is an acronym referring to the first proteins, PER,ARNT, SIM, in which this motif was identified). There are three humanHIFα subunits (HIF-1α, HIF-2α, and HIF-3α) that are oxygen sensitive.Among the three subunits, HIF-1α is the most ubiquitously expressed andinduced by low oxygen concentrations in many cell types. HIF-2α ishighly similar to HIF-1α in both structure and function, but exhibitsmore restricted tissue-specific expression, and might also bedifferentially regulated by nuclear translocation. HIF-3α also exhibitsconservation with HIF-1α and HIF-2α in the HLH and PAS domains. HIFβ(also referred to as ARNT—Aryl Hydrocarbon Receptor NuclearTranslocator), the dimerization partner of the HIFα subunits, isconstitutively expressed in all cell types and is not regulated byoxygen concentration.

SUMMARY OF THE INVENTION

The present invention addresses a need in the art by providing HIF-2αinhibitors as described herein.

In one aspect, the present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is O, S, CHR⁷, NR⁸ or absent;

R¹ is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, acyl or cyano;

R² is nitro, carboxaldehyde, carboxyl, ester, amido, cyano, halo,sulfonyl, alkyl, alkenyl, alkynyl or heteroalkyl;

R³ is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl,amino, carboxaldehyde, carboxylic acid, oxime, ester, amido or acyl; orR² and R³ taken together form a cyclic moiety;

R⁴ is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl,sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;and

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy.

In another aspect, the invention provides a compound of Formula I-A:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is O, S, CHR⁷, NR⁸ or absent;

R² is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo,sulfonyl or alkyl;

R³ is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl,amino, oxime or acyl; or R² and R³ taken together form a cyclic moiety;

R⁴ is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl orsulfoximinyl;

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy;

W¹ is N or CR¹⁰;

R⁹ is cyano, halo, alkyl or alkoxy; and

R¹⁰ is hydrogen, cyano, halo, alkyl or alkoxy.

In another aspect, the invention provides a compound of Formula I-B:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is O, S, CHR⁷, NR⁸ or absent;

R² is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo,sulfonyl or alkyl;

R³ is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl,amino, oxime or acyl; or R² and R³ taken together form a cyclic moiety;

R⁴ is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl orsulfoximinyl;

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy;

R^(c) is hydrogen, cyano, halo, alkyl or alkoxy; and

n′ is 0, 1, 2, 3 or 4.

In yet another aspect, the invention provides a compound of Formula I-C:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is O, S, CHR⁷, NR⁸ or absent;

R¹ is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl;

R⁴ is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl,sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy;

R¹¹ is hydrogen, hydroxy, alkoxy or amino;

R¹² is hydrogen, alkyl, alkenyl or alkynyl; or R¹¹ and R¹² incombination form oxo or oxime;

each of R¹³ is independently selected from the group consisting ofhydrogen, fluoro, chloro, hydroxy, alkyl and heteroalkyl; or two R¹³sand the carbon atom(s) to which they are attached form a 3- to8-membered cycloalkyl or heterocycloalkyl moiety; and

n is 0, 1, 2, 3 or 4.

In some other embodiments of compounds of Formula I-C, R¹ is phenyl,monocyclic heteroaryl or bicyclic heteroaryl. In some embodiments, R¹ isphenyl or pyridyl. In yet other embodiments, R¹ is cycloalkyl orheterocycloalkyl. Compounds of Formula I-C are also provided wherein R¹is substituted with at least one substituent selected from the groupconsisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano.

In still other embodiments of compounds of Formula I-C, R⁴ is cyano,fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In otherembodiments, R⁴ is fluoroalkyl or fluoroalkylsulfonyl. In some otherembodiments, R¹¹ is hydroxy or amino. In further embodiments, R¹¹ ishydroxy. In yet other embodiments, R¹² is hydrogen. In yet anotherembodiment, R¹³ is fluoro and n is 1, 2 or 3.

In some embodiments of compounds of Formula I-C, R⁴ is cyano,fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R¹¹ ishydroxy or amino; and R¹² is hydrogen. In still another embodiment, R¹³is fluoro. In yet another embodiment, Z is O. In some embodiments, Z isS. In still other embodiments, Z is NR⁸. In another embodiment, Z isCHR⁷. In some embodiments, Z is absent.

In some other embodiments of compounds of Formula I-C, R⁴ isfluoroalkyl; n is 0, 1, 2 or 3; Z is O; R¹¹ is hydroxy; and R¹² ishydrogen. In still other embodiments, R⁴ is sulfonyl; n is 0, 1, 2 or 3;Z is O; R¹¹ is hydroxy; and R¹² is hydrogen. In yet other embodiments,R¹ is phenyl, pyridyl, cycloalkyl or heterocycloalkyl. In someembodiments, X is N and Y is CR⁶. In another embodiment, X is CR⁵ and Yis N. In yet another embodiment, X is N and Y is N.

In still another aspect, the invention provides a compound of FormulaI-D, I-E, I-F or I-G:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is O, S, CHR⁷, NR⁸ or absent;

R¹ is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl;

R⁴ is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl,sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy; and

R¹¹ is hydrogen, hydroxy, alkoxy or amino.

In a further aspect, the invention provides a compound of Formula I-H,I-I, I-J or I-K:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is O, S, CHR⁷, NR⁸ or absent;

R¹ is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl;

R⁴ is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl,sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy; and

R¹¹ is hydroxy or amino.

In one aspect, the present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(HR⁷)—, —N(R⁸)—, C₁-C₃alkylene, C₁-C₃ heteroalkylene, C₁-C₃ alkenylene or absent;

R¹ is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, acyl or cyano;

R² is nitro, carboxaldehyde, carboxyl, ester, amido, cyano, halo,sulfonyl, alkyl, alkenyl, alkynyl or heteroalkyl;

R³ is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl,amino, carboxaldehyde, carboxylic acid, oxime, ester, amido or acyl; orR² and R³ taken together form a cyclic moiety;

R⁴ is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl,sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;and

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy.

In another aspect, the invention provides a compound of Formula I-A:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(HR⁷)—, —N(R⁸)—, C₁-C₃alkylene, C₁-C₃ heteroalkylene, C₁-C₃ alkenylene or absent;

R² is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo,sulfonyl or alkyl;

R³ is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl,amino, oxime or acyl; or R² and R³ taken together form a cyclic moiety;

R⁴ is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl orsulfoximinyl;

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy;

W¹ is N or CR¹⁰;

R⁹ is cyano, halo, alkyl or alkoxy; and

R¹⁰ is hydrogen, cyano, halo, alkyl or alkoxy.

In another aspect, the invention provides a compound of Formula I-B:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(HR⁷)—, —N(R⁸)—, C₁-C₃alkylene, C₁-C₃ heteroalkylene, C₁-C₃ alkenylene or absent;

R² is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo,sulfonyl or alkyl;

R³ is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl,amino, oxime or acyl; or R² and R³ taken together form a cyclic moiety;

R⁴ is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl orsulfoximinyl;

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy;

R^(c) is hydrogen, cyano, halo, alkyl or alkoxy; and

n′ is 0, 1, 2, 3 or 4.

In yet another aspect, the invention provides a compound of Formula I-C:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(HR⁷)—, —N(R⁸)—, C₁-C₃alkylene, C₁-C₃ heteroalkylene, C₁-C₃ alkenylene or absent;

R¹ is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl;

R⁴ is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl,sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy;

R¹¹ is hydrogen, halo, hydroxy, alkoxy or amino;

R¹² is hydrogen, alkyl, alkenyl or alkynyl; or R¹¹ and R¹² incombination form ═O, ═CH₂ or ═N(OH);

each of R¹³ is independently selected from the group consisting ofhydrogen, fluoro, chloro, hydroxy, alkyl and heteroalkyl; and two R¹³sand the carbon atom(s) to which they are attached may form a 3- to8-membered cycloalkyl or heterocycloalkyl moiety; and

n is 0, 1, 2, 3 or 4.

In some embodiments of compounds of Formula I-C, R¹² is hydrogen. Infurther embodiments, R¹³ is fluoro and n is 1, 2 or 3. In someembodiments, R¹² is hydrogen, alkyl, alkenyl or alkynyl; or R¹¹ and R¹²in combination form ═O or ═N(OH).

In certain embodiments of compounds of Formula I-C, R⁴ is fluoroalkyl; nis 0, 1, 2 or 3; Z is —O—; R¹¹ is hydroxy; and R¹² is hydrogen. In stillother embodiments, R⁴ is sulfonyl; n is 0, 1, 2 or 3; Z is —O—; R¹¹ ishydroxy; and R¹² is hydrogen.

In still another aspect, the invention provides a compound of FormulaI-D, I-E, I-F or I-G:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(HR⁷)—, —N(R⁸)—, C₁-C₃alkylene, C₁-C₃ heteroalkylene, C₁-C₃ alkenylene or absent;

R¹ is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl;

R⁴ is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl,sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy; and

R¹¹ is hydrogen, halo, hydroxy, alkoxy or amino.

In a further aspect, the invention provides a compound of Formula I-H,I-I, I-J or I-K:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(HR⁷)—, —N(R⁸)—, C₁-C₃alkylene, C₁-C₃ heteroalkylene, C₁-C₃ alkenylene or absent;

R¹ is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl;

R⁴ is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl,sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy; and

R¹¹ is hydroxy or amino.

In some embodiments of compounds of Formula I-C, I-H, I-I, I-J, or I-K,R¹ is phenyl, monocyclic heteroaryl or bicyclic heteroaryl. In someembodiments, R¹ is phenyl or pyridyl. In yet other embodiments, R¹ iscycloalkyl or heterocycloalkyl. In yet another embodiment, R¹ iscyclobutyl. Compounds of Formula I-C, I-H, I-I, I-J, or I-K are alsoprovided wherein R¹ is substituted with at least one substituentselected from the group consisting of halo, hydroxy, C₁-C₄ alkyl, C₁-C₄alkoxy and cyano. In some embodiments, R¹ is substituted with one to sixfluorines. In certain embodiments, R¹ is selected from

In certain embodiments of compounds of Formula I-C, I-H, I-I, I-J, orI-K, R⁴ is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl,sulfoximinyl, or fluroalkylsulfonyl. In other embodiments, R⁴ isfluoroalkyl or fluoroalkylsulfonyl. In some other embodiments, R¹¹ ishydroxy or amino. In further embodiments, R¹¹ is hydroxy. In yet otherembodiments, R¹² is hydrogen. In yet another embodiment, R¹³ is fluoroand n is 1, 2 or 3.

In some embodiments of compounds of Formula I-C, I-H, I-I, I-J, or I-K,R⁴ is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl orsulfoximinyl; R¹¹ is hydroxy or amino; and R¹² is hydrogen. In stillanother embodiment, R¹³ is fluoro. In yet another embodiment, Z is —O—.In some embodiments, Z is —S—. In still other embodiments, Z is —N(R⁸)—.In another embodiment, Z is —C(HR⁷)—. In some embodiments, Z is absent.

In some other embodiments of compounds of Formula I-C, I-H, I-I, I-J, orI-K, R⁴ is fluoroalkyl; Z is —O—; and R¹¹ is hydroxy. In still otherembodiments, R⁴ is sulfonyl; Z is —O—; and R¹¹ is hydroxy. In yet otherembodiments, R¹ is phenyl, pyridyl, cycloalkyl or heterocycloalkyl. Insome embodiments, R¹ is cyclobutyl. In some embodiments, R¹ issubstituted with at least one substituent selected from the groupconsisting of halo, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano. Insome embodiments, X is N and Y is CR⁶. In another embodiment, X is CR⁵and Y is N. In yet another embodiment, X is N and Y is N.

In yet another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound disclosed herein and apharmaceutically acceptable carrier.

In still yet another aspect, the present invention provides a method forinhibiting HIF-2α signaling output, comprising contacting HIF-2α with aneffective amount of a compound disclosed herein.

In another aspect, the present invention provides a method forinhibiting HIF-2α, comprising contacting HIF-2α with an effective amountof a compound disclosed herein, wherein inhibition of HIF-2α isevidenced by a reduction of one or more biological effects selected fromthe group consisting of heterodimerization of HIF-2α to ARNT, HIF-2αtarget gene expression, VEGF gene expression, VEGF protein secretion,and the mRNA level of a HIF-2α-regulated gene.

In yet another aspect, the present invention provides a method forinhibiting HIF-2α, comprising contacting HIF-2α with an effective amountof a compound disclosed herein, thereby reducing the heterodimerizationof HIF-2α to ARNT but not heterodimerization of HIF-1α to ARNT.

In practicing any of the methods described herein, the contacting mayfurther comprise contacting a cell that expresses HIF-2α. In some otherembodiments, the method further comprises administering a secondtherapeutic agent to the cell. In other embodiments, the contacting stepof the method may take place in vivo. In another embodiment, thecontacting step of the method may take place in vitro.

In some other aspects, the present invention provides a method fortreating a condition associated with HIF-2α, comprising administering toa subject in need thereof an effective amount of a compound disclosedherein. In some embodiments, the present invention provides a method fortreating a neoplastic condition in a subject, comprising administeringto said subject a therapeutically effective amount of a pharmaceuticalcomposition of a compound disclosed herein. In some embodiments, amethod for treating renal cell carcinoma (RCC) in a subject, comprisingadministering to said subject a therapeutically effective amount of apharmaceutical composition of a compound disclosed herein, is provided.In a further embodiment, said subject may be a human. In yet anotherembodiment, said renal cell carcinoma may be clear cell renal cellcarcinoma (ccRCC).

In certain aspects, the present invention provides a method of treatingvon Hippel-Lindau (VHL) disease, comprising administering to a subjectin need thereof an effective amount of a compound described herein.

In still another aspect, the present invention provides a kit comprisinga pharmaceutical composition of a compound disclosed herein andinstructions for using the composition to treat a subject suffering fromrenal cell carcinoma.

INCORPORATION BY REFERENCE

All publications, patents and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows decreased mRNA levels of HIF-2α target genes in 786-Oxenografts following treatment with compounds 22, 34, or 37.

FIG. 2 shows decreased levels of human VEGF in the plasma of 786-Oxenograft bearing mice treated with compound 22, 34, or 37.

DETAILED DESCRIPTION OF THE INVENTION

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes and substitutions will now occur to those skilled inthe art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe appended claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference.

As used in the specification and claims, the singular form “a”, “an” and“the” includes plural references unless the context clearly dictatesotherwise.

As used herein, “agent” or “biologically active agent” refers to abiological, pharmaceutical, or chemical compound or other moiety.Non-limiting examples include a simple or complex organic or inorganicmolecule, a peptide, a protein, an oligonucleotide, an antibody, anantibody derivative, antibody fragment, a vitamin derivative, acarbohydrate, a toxin, or a chemotherapeutic compound. Various compoundscan be synthesized, for example, small molecules and oligomers (e.g.,oliopeptides and oligonucleotides), and synthetic organic compoundsbased on various core structures. In addition, various natural sourcescan provide compounds for screening, such as plant or animal extracts,and the like. A skilled artisan can readily recognize that there is nolimit as to the structural nature of the agents of the presentinvention.

The terms “antagonist” and “inhibitor” are used interchangeably, andthey refer to a compound having the ability to inhibit a biologicalfunction of a target protein, whether by inhibiting the activity orexpression of the target protein. Accordingly, the terms “antagonist”and “inhibitors” are defined in the context of the biological role ofthe target protein. While preferred antagonists herein specificallyinteract with (e.g., bind to) the target, compounds that inhibit abiological activity of the target protein by interacting with othermembers of the signal transduction pathway of which the target proteinis a member are also specifically included within this definition. Apreferred biological activity inhibited by an antagonist is associatedwith the development, growth, or spread of a tumor, or an undesiredimmune response as manifested in autoimmune disease.

The term “cell proliferation” refers to a phenomenon by which the cellnumber has changed as a result of division. This term also encompassescell growth by which the cell morphology has changed (e.g., increased insize) consistent with a proliferative signal.

The terms “co-administration,” “administered in combination with,” andtheir grammatical equivalents, encompass administration of two or moreagents to an animal so that both agents and/or their metabolites arepresent in the animal at the same time. Co-administration includessimultaneous administration in separate compositions, administration atdifferent times in separate compositions, or administration in acomposition in which both agents are present.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound described herein that is sufficient toeffect the intended application including but not limited to diseasetreatment, as defined below. The therapeutically effective amount mayvary depending upon the intended application (in vitro or in vivo), orthe subject and disease condition being treated, e.g., the weight andage of the subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g., reduction ofplatelet adhesion and/or cell migration. The specific dose will varydepending on the particular compounds chosen, the dosing regimen to befollowed, whether it is administered in combination with othercompounds, timing of administration, the tissue to which it isadministered, and the physical delivery system in which it is carried.

As used herein, the terms “treatment”, “treating”, “palliating” and“ameliorating” are used interchangeably. These terms refer to anapproach for obtaining beneficial or desired results including, but arenot limited to, therapeutic benefit and/or a prophylactic benefit. Bytherapeutic benefit is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient can still be afflicted with the underlying disorder. Forprophylactic benefit, the pharmaceutical compositions may beadministered to a patient at risk of developing a particular disease, orto a patient reporting one or more of the physiological symptoms of adisease, even though a diagnosis of this disease may not have been made.

A “therapeutic effect,” as used herein, encompasses a therapeuticbenefit and/or a prophylactic benefit as described above. A prophylacticeffect includes delaying or eliminating the appearance of a disease orcondition, delaying or eliminating the onset of symptoms of a disease orcondition, slowing, halting, or reversing the progression of a diseaseor condition, or any combination thereof.

The term “pharmaceutically acceptable” means that a chemical entity,such as a compound, a carrier, an additive or a salt, is acceptable forbeing administrated to a subject.

The term “pharmaceutically acceptable salt” refers to salts derived froma variety of organic and inorganic counter ions well known in the art.Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids. Inorganic acids from which salts canbe derived include, for example, hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acidsfrom which salts can be derived include, for example, acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and thelike. Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases. Inorganic bases from which salts can bederived include, for example, sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum, and thelike. Organic bases from which salts can be derived include, forexample, primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines, basicion exchange resins, and the like, specifically such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. In some embodiments, the pharmaceutically acceptable baseaddition salt is chosen from ammonium, potassium, sodium, calcium, andmagnesium salts.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes any and all solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions of theinvention is contemplated. Supplementary active ingredients can also beincorporated into the compositions.

The term “selective inhibition” or “selectively inhibit” as applied to abiologically active agent refers to the agent's ability to selectivelyreduce the target signaling activity as compared to off-target signalingactivity, via direct or indirect interaction with the target.

The term “subject” includes, but is not limited to, humans of any agegroup, e.g., a pediatric subject (e.g., infant, child or adolescent) oradult subject (e.g., young adult, middle-aged adult or senior adult))and/or other primates (e.g., cynomolgus monkeys or rhesus monkeys);mammals, including commercially relevant mammals such as cattle, pigs,horses, sheep, goats, cats, and/or dogs; and/or birds, includingcommercially relevant birds such as chickens, ducks, geese, quail,and/or turkeys. The methods described herein can be useful in both humantherapeutics and veterinary applications. In some embodiments, thepatient is a mammal, and in some embodiments, the patient is human.

“Radiation therapy” or “radiation treatment” means exposing a patient,using routine methods and compositions known to the practitioner, toradiation emitters such as alpha-particle emitting radionucleotides(e.g., actinium and thorium radionuclides), low linear energy transfer(LET) radiation emitters (e.g., beta emitters), conversion electronemitters (e.g., strontium-89 and samarium-153-EDTMP), or high-energyradiation, including without limitation x-rays, gamma rays, andneutrons.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers advantages of solubility,tissue compatibility or delayed release in a mammalian organism (see,e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al.,“Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14,and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche,American Pharmaceutical Association and Pergamon Press, 1987, both ofwhich are incorporated in full by reference herein. The term “prodrug”is also meant to include any covalently bonded carriers, which releasethe active compound in vivo when such prodrug is administered to amammalian subject. Prodrugs of an active compound, as described herein,may be prepared by modifying functional groups present in the activecompound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent active compound. Prodrugsinclude compounds wherein a hydroxy, amino or mercapto group is bondedto any group that, when the prodrug of the active compound isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of an alcohol or acetamide, formamide and benzamidederivatives of an amine functional group in the active compound and thelike.

The term “in vivo” refers to an event that takes place in a subject'sbody.

The term “in vitro” refers to an event that takes place outside of asubject's body. For example, an in vitro assay encompasses any assay runoutside of a subject's body. In vitro assays encompass cell-based assaysin which cells alive or dead are employed. In vitro assays alsoencompass a cell-free assay in which no intact cells are employed.

The term “HIF-2α” refers to a monomeric protein that contains severalconserved structured domains: basic helix-loop-helix (bHLH), and twoPer-ARNT-Sim (PAS) domains designated PAS-A and PAS-B, in addition toC-terminal regulatory regions. “HIF-2α” is also alternatively known byseveral other names in the scientific literature, including EndothelialPAS Domain Protein 1 (EPAS1), HIF-2A, PASD2, HIF-2-Alpha, HIF-2-Alpha,HLF, Hypoxia-Inducible Factor 2-Alpha, HIF-1alpha-Like Factor, and MOP2.As a member of the bHLH/PAS family of transcription factors, “HIF-2α”forms an active heterodimeric transcription factor complex by binding tothe ARNT (also known as HIF-1β) protein through non-covalentinteractions. In some embodiments, “HIF-2α” may refer to a fragment ofthe native protein. In some further embodiments, the fragment mayinclude residues 239 to 348 of the native protein sequence.

The term “scintillation proximity assay” (SPA) refers to a homogeneousassay in which light is emitted when a radiolabeled ligand is broughtinto close proximity to a radiosensitive bead. The assay typicallycontains a target protein that contains a tag (e.g., His Tag,Glutathione S-transferase Tag). The tag on the protein is used to bindthe target protein to the scintillation bead. Radio-labeled ligand(e.g., labeled with tritium) that binds to the protein is now in closeproximity to the bead, and when the radio-label (e.g., tritium) decays,the high energy particle hits the bead resulting in the emission oflight that is detected by a detector, such as photomultiplier tube orCCD camera. When unlabeled ligands or compounds that bind to the proteinare used in the assay, they displace the radio-labeled ligand, resultingin loss of signal. For a general reference describing the assay, seePark, et al. Analytical Biochemistry 269: 94-104, 1999.

“HIF-2α activity” as used herein has its ordinary meaning in the art.HIF-2α activity, for example, includes activation of gene transcriptionmediated by HIF-2α.

The term “inhibiting HIF-2α activity”, as used herein, refers toslowing, reducing, altering, as well as completely eliminating and/orpreventing HIF-2α activity.

The term “alkyl” refers to a straight or branched hydrocarbon chainradical comprising carbon and hydrogen atoms, containing nounsaturation, and having from one to ten carbon atoms (e.g., C₁-C₁₀alkyl). Whenever it appears herein, a numerical range such as “1 to 10”refers to each integer in the given range; e.g., “1 to 10 carbon atoms”means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms,3 carbon atoms, etc., up to and including 10 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated. In some embodiments, it is a C₁-C₄alkyl group. Typical alkyl groups include, but are in no way limited to,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl,decyl, and the like. The alkyl is attached to the rest of the moleculeby a single bond, for example, methyl (Me), ethyl (Et), n-propyl,1-methylethyl, (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl(t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Unless statedotherwise specifically in the specification, an alkyl group isoptionally substituted by one or more of substituents whichindependently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(═O)R^(a), —OC(═O)OR^(a),—OC(═O)N(R^(a))₂, —N(R^(a))₂, —C(═O)OR^(a), —C(═O)R^(a),—C(═O)N(R^(a))₂, —N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))C(═O)R^(a),—N(R^(a))S(═O)_(t)R^(a) (where t is 1 or 2), —N(R^(a))S(═O)_(t)N(R^(a))₂(where t is 1 or 2), —S(═O)_(t)R^(a) (where t is 1 or 2),—S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —PO₃(R^(a))₂, —OPO₃WY (where Wand Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodiumor potassium) or —OPO₃Z (where Z is calcium, magnesium or iron), whereineach R^(a) is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl,heteroaryl or heteroarylalkyl.

The term “fluoroalkyl” refers to an alkyl group substituted with one ormore fluorine atoms. In some embodiments, it is a C₁-C₄ alkyl groupsubstituted with one or more fluorine atoms. Typical fluoroalkyl groupsinclude, but are in no way limited to, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃,—CH₂CHF₂, —CH₂CH₂F, —CHFCH₃ and —CF₂CH₃.

The term “alkenyl” refers to a straight or branched hydrocarbon chainradical group comprising carbon and hydrogen atoms, containing at leastone double bond, and having from two to ten carbon atoms (i.e., C₂-C₁₀alkenyl). Whenever it appears herein, a numerical range such as “2 to10” refers to each integer in the given range; e.g., “2 to 10 carbonatoms” means that the alkenyl group may contain 2 carbon atoms, 3 carbonatoms, etc., up to and including 10 carbon atoms. In certainembodiments, an alkenyl comprises two to eight carbon atoms (i.e., C₂-C₈alkenyl). In other embodiments, an alkenyl comprises two to five carbonatoms (i.e., C₂-C₅ alkenyl). The alkenyl is attached to the rest of themolecule by a single bond, for example, ethenyl (i.e., vinyl),prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.Unless stated otherwise specifically in the specification, an alkenylgroup is optionally substituted by one or more of the followingsubstituents: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(═O)R^(a), —OC(═O)OR^(a),—OC(═O)N(R^(a))₂, —N(R^(a))₂, —C(═O)OR^(a), —C(═O)R^(a),—C(═O)N(R^(a))₂, —N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))C(═O)R^(a),—N(R^(a))S(═O)_(t)R^(a) (where t is 1 or 2), —N(R^(a))S(═O)_(t)N(R^(a))₂(where t is 1 or 2), —S(═O)_(t)R^(a) (where t is 1 or 2),—S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —PO₃(R^(a))₂, —OPO₃WY (where Wand Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodiumor potassium) or —OPO₃Z (where Z is calcium, magnesium or iron), whereineach R^(a) is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl,heteroaryl or heteroarylalkyl.

The term “alkynyl” refers to a straight or branched hydrocarbon chainradical group comprising carbon and hydrogen atoms, containing at leastone triple bond, and having from two to ten carbon atoms (i.e., C₂-C₁₀alkynyl). In some embodiments, an alkynyl group may contain one or moredouble bonds. Whenever it appears herein, a numerical range such as “2to 10” refers to each integer in the given range; e.g., “2 to 10 carbonatoms” means that the alkynyl group may contain 2 carbon atoms, 3 carbonatoms, etc., up to and including 10 carbon atoms. In certainembodiments, an alkynyl comprises two to eight carbon atoms (i.e., C₂-C₈alkynyl). In other embodiments, an alkynyl has two to five carbon atoms(i.e., C₂-C₅ alkynyl). The alkynyl is attached to the rest of themolecule by a single bond, for example, ethynyl, propynyl, butynyl,pentynyl, hexynyl, and the like. Unless stated otherwise specifically inthe specification, an alkynyl group is optionally substituted by one ormore of the following substituents: alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a),—SR^(a), —OC(═O)R^(a), —OC(═O)OR^(a), —OC(═O)N(R^(a))₂, —N(R^(a))₂,—C(═O)OR^(a), —C(═O)R^(a), —C(═O)N(R^(a))₂, —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)N(R^(a), —N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))C(═O)R^(a),—N(R^(a))S(═O)_(t)R^(a) (where t is 1 or 2), —N(R^(a))S(═O)_(t)N(R^(a))₂(where t is 1 or 2), —S(═O)_(t)R^(a) (where t is 1 or 2),—S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —PO₃(R^(a))₂, —OPO₃WY (where Wand Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodiumor potassium) or —OPO₃Z (where Z is calcium, magnesium or iron), whereineach R^(a) is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl,heteroaryl or heteroarylalkyl.

The term “aromatic” or “aryl” refers to an aromatic radical with six toten ring atoms (i.e., C₆-C₁₀ aromatic or C₆-C₁₀ aryl) which has at leastone ring having a conjugated pi electron system which is carbocyclic(e.g., phenyl, fluorenyl, and naphthyl). Whenever it appears herein, anumerical range such as “6 to 10” refers to each integer in the givenrange; e.g., “6 to 10 ring atoms” means that the aryl group may consistof 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms.The term includes monocyclic or fused-ring polycyclic (i.e., rings whichshare adjacent pairs of ring atoms) groups. Unless stated otherwisespecifically in the specification, an aryl moiety is optionallysubstituted by one or more substituents which are independently: alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(═O)R^(a), —OC(═O)OR^(a), —OC(═O)N(R^(a))₂,—N(R^(a))₂, —C(═O)OR^(a), —C(═O)R^(a), —C(═O)N(R^(a))₂,—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))C(═O)R^(a),—N(R^(a))S(═O)_(t)R^(a) (where t is 1 or 2), —N(R^(a))S(═O)_(t)N(R^(a))₂(where t is 1 or 2), —S(═O)_(t)R^(a) (where t is 1 or 2),—S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —PO₃(R^(a))₂, —OPO₃WY (where Wand Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodiumor potassium) or —OPO₃Z (where Z is calcium, magnesium or iron), whereineach R^(a) is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl,heteroaryl or heteroarylalkyl.

“Aralkyl” or “arylalkyl” refers to an (aryl)alkyl-radical wherein thearylalkyl moiety is attached via the alkyl portion of the moiety. Aryland alkyl are as disclosed herein and are optionally substituted by oneor more of the substituents described as suitable substituents for aryland alkyl, respectively.

The term “heteroaryl” or, alternatively, “heteroaromatic” refers to a 5-to 18-membered aromatic radical (i.e., C₅-C₁₈ heteroaryl) that includesone or more ring heteroatoms selected from nitrogen, oxygen and sulfur,and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ringsystem. Whenever it appears herein, a numerical range such as “5 to 18”refers to each integer in the given range; e.g., “5 to 18 ring atoms”means that the heteroaryl group may consist of 5 ring atoms, 6 ringatoms, etc., up to and including 18 ring atoms. An N-containing“heteroaromatic” or “heteroaryl” moiety refers to an aromatic group inwhich at least one of the skeletal atoms of the ring is a nitrogen atom.The polycyclic heteroaryl group may be fused or non-fused. Theheteroatom(s) in the heteroaryl radical, e.g., nitrogen or sulfur, isoptionally oxidized. One or more nitrogen atoms, if present, areoptionally quaternized. The heteroaryl is attached to the rest of themolecule through any atom of the ring(s). Examples of heteroarylsinclude, but are not limited to, azepinyl, acridinyl, benzimidazolyl,benzindolyl, 1,3-benzodioxolyl, benzooxazolyl, benzo[d]thiazolyl,benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl,1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl,benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl,benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, aheteroaryl moiety is optionally substituted by one or more substituentswhich are independently alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a),—SR^(a), —OC(═O)R^(a), —OC(═O)OR^(a), —OC(═O)N(R^(a))₂, —N(R^(a))₂,—C(═O)OR^(a), —C(═O)R^(a), —C(═O)N(R^(a))₂, —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))C(═O)R^(a), —N(R^(a))S(═O)_(t)R^(a) (where t is 1 or 2),—N(R^(a))S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —S(═O)_(t)R^(a) (wheret is 1 or 2), —S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —PO₃(R^(a))₂,—OPO₃WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl,lithium, sodium or potassium) or —OPO₃Z (where Z is calcium, magnesiumor iron), wherein each R^(a) is independently hydrogen, alkyl,fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl.Examples of monocylic heteroaryls include, but are not limited to,imidazolyl, pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, thiazolyl,furanyl and thienyl.

Substituted heteroaryl also includes ring systems substituted with oneor more oxide substituents, such as pyridinyl N-oxides.

“Heteroarylalkyl” refers to a moiety having a heteroaryl moiety, asdescribed herein, connected to an alkyl moiety, as described herein,wherein the connection to the remainder of the molecule is through thealkyl group. Heteroaryl and alkyl are as disclosed herein and areoptionally substituted by one or more of the substituents described assuitable substituents for heteroaryl and alkyl, respectively.

The term “acyl” refers to a —C(═O)R radical, wherein R is alkyl,cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocycloalkyl, whichare as described herein. The R group is attached to the parent structurethrough the carbonyl functionality. In some embodiments, it is a C₁-C₁₀acyl radical which refers to the total number of chain or ring atoms ofthe alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl or heterocycloalkylportion of the acyl group plus the carbonyl carbon of acyl, i.e. ring orchain atoms plus carbonyl. If the R radical is heteroaryl orheterocycloalkyl, the hetero ring or chain atoms contribute to the totalnumber of chain or ring atoms. Unless stated otherwise specifically inthe specification, the “R” of an acyl group is optionally substituted byone or more substituents which independently are: alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a),—SR^(a), —OC(═O)R^(a), —OC(═O)OR^(a), —OC(═O)N(R^(a))₂, —N(R^(a))₂,—C(═O)OR^(a), —C(═O)R^(a), —C(═O)N(R^(a))₂, —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))C(═O)R^(a), —N(R^(a))S(═O)_(t)R^(a) (where t is 1 or 2),—N(R^(a))S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —S(═O)_(t)R^(a) (wheret is 1 or 2), —S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —PO₃(R^(a))₂,—OPO₃WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl,lithium, sodium or potassium) or —OPO₃Z (where Z is calcium, magnesiumor iron), wherein each R^(a) is independently hydrogen, alkyl,fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl.

The term “halo”, “halide”, or alternatively, “halogen” means fluoro,chloro, bromo or iodo. The terms “haloalkyl,” “haloalkenyl,”“haloalkynyl” and “haloalkoxy” include alkyl, alkenyl, alkynyl andalkoxy structures that are substituted with one or more halo groups orwith combinations thereof. For example, the terms “fluoroalkyl” and“fluoroalkoxy” refer to haloalkyl and haloalkoxy groups, respectively,in which the halo is fluoro. Examples of fluoroalkyl include, but arenot limited to, —CH₂F, —CHF₂, —CF₃, —CF₂CH₃, —CH₂CF₃, and —CF₂CF₃. Thealkyl part of the haloalkyl radical may be optionally substituted asdefined above for an alkyl group.

The term “cyano” refers to a —CN radical.

The term “alkoxy” refers to an —O-alkyl radical, including from whereinalkyl is as described herein and contains 1 to 10 carbon atoms (i.e.,C₁-C₁₀ alkoxy) of a straight, branched, or cyclic configuration andcombinations thereof attached to the parent structure through an oxygen.Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy,cyclohexyloxy and the like. Whenever it appears herein, a numericalrange such as “1 to 10” refers to each integer in the given range; e.g.,“1 to 10 carbon atoms” means that the alkyl group may consist of 1carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including10 carbon atoms. In some embodiments, it is a C₁-C₄ alkoxy group. Unlessstated otherwise specifically in the specification, an alkoxy moiety maybe substituted by one or more of the substituents described as suitablesubstituents for an alkyl radical.

The term “sp³ hybridized carbon” refers to a carbon atom that is bondedto four other atoms. sp³ hybridization results from the combination ofthe s orbital and all three p orbitals in the second energy level ofcarbon. It results in four equivalent orbitals and the geometricarrangement of those four orbitals is tetrahedral.

The term “sulfonyl” refers to a —S(═O)₂R^(a) radical, wherein R^(a) isselected from the group consisting of alkyl, amino, cycloalkyl, aryl,heteroalkyl, heteroaryl (bonded through a ring carbon) andheterocycloalkyl (bonded through a ring carbon). Unless stated otherwisespecifically in the specification, the R^(a) group may be substituted byone or more of the substituents described as suitable substituents foran alkyl, an aryl or a heteroaryl radical.

The term “sulfoximinyl” refers to a —S(═O)(═NR^(a))R^(b) radical,wherein R^(a) is selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, cyano, carbamoyl, acyl, heteroaryl (bonded through aring carbon) and heterocycloalkyl (bonded through a ring carbon) andR^(b) is independently selected from the group consisting of alkyl,cycloalkyl, aryl, heteroalkyl, heteroaryl (bonded through a ring carbon)and heterocycloalkyl (bonded through a ring carbon). Unless statedotherwise specifically in the specification, the R^(a) and R^(b) groupsmay be substituted by one or more of the substituents described assuitable substituents for an alkyl, an aryl or a heteroaryl radical.

“Sulfonamide,” “sulfonamidyl” or “sulfonamido” refers to a—S(═O)₂N(R^(a))₂ radical, wherein each R^(a) is selected independentlyfrom the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl,aryl, heteroaryl and heterocycloalkyl. The R^(a) groups in —N(R^(a))₂ ofthe —S(═O)₂—N(R^(a))₂ radical may be taken together with the nitrogen towhich it is attached to form a 4-, 5-, 6-, or 7-membered ring. In someembodiments, it is a C₁-C₁₀ sulfonamido, wherein each R^(a) insulfonamido contains 1 carbon, 2 carbons, 3 carbons or 4 carbons total.A sulfonamido group is optionally substituted by one or more of thesubstituents described for alkyl, cycloalkyl, aryl and heteroaryl,respectively.

The term “fluoroalkylsulfonyl” refers to a —S(═O)₂R^(a) radical, whereinR^(a) is fluoroalkyl. In some embodiments, R^(a) is C₁-C₄ alkyl,substituted with one or more fluorines.

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromaticradical that contains carbon and hydrogen, and may be saturated, orpartially unsaturated. Cycloalkyl groups include groups having from 3 to10 ring atoms (e.g., C₃-C₁₀ cycloalkyl). Whenever it appears herein, anumerical range such as “3 to 10” refers to each integer in the givenrange; e.g., “3 to 10 carbon atoms” means that the cycloalkyl group mayconsist of 3 carbon ring atoms, 4 carbon ring atoms, 5 carbon ringatoms, etc., up to and including 10 carbon ring atoms. In someembodiments, it is a C₃-C₈ cycloalkyl radical. In some embodiments, itis a C₃-C₅ cycloalkyl radical. Illustrative examples of cycloalkylgroups include, but are not limited to the following moieties:cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl,norbornyl, and the like. Unless stated otherwise specifically in thespecification, a cycloalkyl group is optionally substituted by one ormore substituents which independently are: alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a),—SR^(a), —OC(═O)R^(a), —OC(═O)OR^(a), —OC(═O)N(R^(a))₂, —N(R^(a))₂,—C(═O)OR^(a), —C(═O)R^(a), —C(═O)N(R^(a))₂, —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))C(═O)R^(a), —N(R^(a))S(═O)_(t)R^(a) (where t is 1 or 2),—N(R^(a))S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —S(═O)_(t)R^(a) (wheret is 1 or 2), —S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —PO₃(R^(a))₂,—OPO₃WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl,lithium, sodium or potassium) or —OPO₃Z (where Z is calcium, magnesiumor iron), wherein each R^(a) is independently hydrogen, alkyl,fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl.

The term “heterocyclyl” or “heterocycloalkyl” refers to a stable 3- to18-membered nonaromatic ring (e.g., C₃-C₁₈ heterocycloalkyl) radicalthat comprises two to twelve ring carbon atoms and from one to sixheteroatoms selected from nitrogen, oxygen and sulfur. Whenever itappears herein, a numerical range such as “3 to 18” refers to eachinteger in the given range; e.g., “3 to 18 ring atoms” means that theheterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc.,up to and including 18 ring atoms. In some embodiments, it is a C₅-C₁₀heterocycloalkyl. In some embodiments, it is a C₄-C₁₀ heterocycloalkyl.In some embodiments, it is a C₃-C₁₀ heterocycloalkyl. Unless statedotherwise specifically in the specification, the heterocycloalkylradical may be a monocyclic, bicyclic, tricyclic or tetracyclic ringsystem, which may include fused or bridged ring systems. The heteroatomsin the heterocycloalkyl radical may be optionally oxidized. One or morenitrogen atoms, if present, may optionally be quaternized. Theheterocycloalkyl radical may be partially or fully saturated. Theheterocycloalkyl may be attached to the rest of the molecule through anyatom of the ring(s). Examples of such heterocycloalkyl radicals include,but are not limited to, 6,7-dihydro-5H-cyclopenta[b]pyridine,dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, a heterocycloalkyl moiety is optionally substituted byone or more substituents which independently are: alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a),—SR^(a), —OC(═O)R^(a), —OC(═O)OR^(a), —OC(═O)N(R^(a))₂, —N(R^(a))₂,—C(═O)OR^(a), —C(═O)R^(a), —C(═O)N(R^(a))₂, —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))C(═O)R^(a), —N(R^(a))S(═O)_(t)R^(a) (where t is 1 or 2),—N(R^(a))S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —S(═O)_(t)R^(a) (wheret is 1 or 2), —S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —PO₃(R^(a))₂,—OPO₃WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl,lithium, sodium or potassium) or —OPO₃Z (where Z is calcium, magnesiumor iron), wherein each R^(a) is independently hydrogen, alkyl,fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl.

“Heterocycloalkyl” also includes bicyclic ring systems wherein onenon-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2carbon atoms in addition to 1-3 heteroatoms independently selected fromoxygen, sulfur and nitrogen, as well as combinations comprising at leastone of the foregoing heteroatoms; the other ring, usually with 3 to 7ring atoms, optionally contains 1-3 heteroatoms independently selectedform oxygen, sulfur and nitrogen and is not aromatic.

The terms “heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” includeoptionally substituted alkyl, alkenyl and alkynyl radicals, whichrespectively have one or more skeletal chain atoms selected from an atomother than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus orcombinations thereof. A numerical range, which refers to the chainlength in total, may be given. For example, C₃-C₄ heteroalkyl has achain length of 3-4 atoms. For example, a —CH₂OOCH₂CH₃ radical isreferred to as a “C₄ heteroalkyl”, which includes the heteroatom in theatom chain length description. Connection to the rest of the moleculemay be through either a heteroatom or a carbon in the heteroalkyl chain.A heteroalkyl may be a substituted alkyl. The same definition applies toheteroalkenyl or heteroalkynyl. Unless otherwise stated in thespecification, a heteroalkyl group may be substituted with one or moresubstituents which independently are: alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a),—SR^(a), —OC(═O)R^(a), —OC(═O)OR^(a), —OC(═O)N(R^(a))₂, —N(R^(a))₂,—C(═O)OR^(a), —C(═O)R^(a), —C(═O)N(R^(a))₂, —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))C(═O)R^(a), —N(R^(a))S(═O)_(t)R^(a) (where t is 1 or 2),—N(R^(a))S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —S(═O)_(t)R^(a) (wheret is 1 or 2), —S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —PO₃(R^(a))₂,—OPO₃WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl,lithium, sodium or potassium) or —OPO₃Z (where Z is calcium, magnesiumor iron), wherein each R^(a) is independently hydrogen, alkyl,fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl.

The term “amino” or “amine” refers to a —N(R^(a))₂ radical group, whereeach R^(a) is independently hydrogen, alkyl, heteroalkyl, fluoroalkyl,cycloalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl,heteroaryl or heteroarylalkyl, unless stated otherwise specifically inthe specification. When a —N(R^(a))₂ group has two R^(a) other thanhydrogen, they can be combined with the nitrogen atom to form a 3-, 4-,5-, 6-, 7- or 8-membered ring. For example, —N(R^(a))₂ is meant toinclude, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. Unlessstated otherwise specifically in the specification, an amino group isoptionally substituted by one or more substituents which independentlyare: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(═O)R^(a), —OC(═O)OR^(a), —OC(═O)N(R^(a))₂,—N(R^(a))₂, —C(═O)OR^(a), —C(═O)R^(a), —C(═O)N(R^(a))₂,—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))C(═O)R^(a),—N(R^(a))S(═O)_(t)R^(a) (where t is 1 or 2), —N(R^(a))S(═O)_(t)N(R^(a))₂(where t is 1 or 2), —S(═O)_(t)R^(a) (where t is 1 or 2),—S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —PO₃(R^(a))₂, —OPO₃WY (where Wand Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodiumor potassium) or —OPO₃Z (where Z is calcium, magnesium or iron), whereineach R^(a) is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl,heteroaryl or heteroarylalkyl.

The term “substituted amino” also refers to N-oxides of N(R^(a))₂ asdescribed above. N-oxides can be prepared by treatment of thecorresponding amino group with, for example, hydrogen peroxide orm-chloroperoxybenzoic acid. The person skilled in the art is familiarwith reaction conditions for carrying out the N-oxidation.

The term “acyloxy” refers to a RC(═O)O— radical wherein R is alkyl,cycloalkyl, aryl, heteroalkyl, heteroaryl or heterocycloalkyl, which areas described herein. In some embodiments, it is a C₁-C₄ acyloxy radical,which refers to the total number of chain or ring atoms of the alkyl,cycloalkyl, aryl, heteroalkyl, heteroaryl or heterocycloalkyl portion ofthe acyloxy group plus the carbonyl carbon of acyl, i.e., the other ringor chain atoms plus carbonyl. If the R radical is heteroaryl orheterocycloalkyl, the hetero ring or chain atoms contribute to the totalnumber of chain or ring atoms. Unless stated otherwise specifically inthe specification, the “R” of an acyloxy group is optionally substitutedby one or more of the following substituents: alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a),—SR^(a), —OC(═O)R^(a), —OC(═O)OR^(a), —OC(═O)N(R^(a))₂, —N(R^(a))₂,—C(═O)OR^(a), —C(═O)R^(a), —C(═O)N(R^(a))₂, —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))C(═O)R^(a), —N(R^(a))S(═O)_(t)R^(a) (where t is 1 or 2),—N(R^(a))S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —S(═O)_(t)R^(a) (wheret is 1 or 2), —S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —PO₃(R^(a))₂,—OPO₃WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl,lithium, sodium or potassium) or —OPO₃Z (where Z is calcium, magnesiumor iron), wherein each R^(a) is independently hydrogen, alkyl,fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl.

The term “amide” or “amido” refers to a chemical moiety with formula—C(═O)N(R^(a))₂ or —NR^(a)C(═O)R^(a), wherein each of R^(a) isindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheterocycloalkyl. Two R^(a)s may optionally be taken together with thenitrogen to which it is attached to form a 4-10 membered ring. In someembodiments, it is a C₁-C₄ amido or amide radical, which includes theamide carbonyl in the total number of carbons in the radical. Unlessstated otherwise specifically in the specification, an amido group isoptionally substituted independently by one or more of the substituentsas described herein for alkyl, cycloalkyl, aryl, heteroaryl, orheterocycloalkyl. An amide may be an amino acid or a peptide moleculeattached to a compound having an amine or a carboxylic acid moiety,thereby forming a prodrug. Any amine, hydroxy or carboxyl side chain onthe compounds described herein can be amidified. The procedures andspecific groups to make such amides are known to those of skilled in theart and can readily be found in reference sources such as Wuts, Greene'sProtective Groups in Organic Synthesis, 5^(th) Ed., Wiley, New York,N.Y., 2014, which is incorporated herein by reference in its entirety.

“Carboxaldehyde” refers to a —C(═O)H radical.

“Carboxyl” refers to a —C(═O)OH radical.

“Ester” refers to a chemical radical of formula —C(═O)OR, where R isselected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bondedthrough a ring carbon). Any amine, hydroxy, or carboxyl side chain onthe compounds described herein can be esterified. The procedures andspecific groups to make such esters are known to those skilled in theart and can readily be found in reference sources such as Wuts, Greene'sProtective Groups in Organic Synthesis, 5^(th) Ed., Wiley, New York,N.Y., 2014, which is incorporated herein by reference in its entirety.Unless stated otherwise specifically in the specification, an estergroup is optionally substituted by one or more substituents whichindependently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(═O)R^(a), —OC(═O)OR^(a),—OC(═O)N(R^(a))₂, —N(R^(a))₂, —C(═O)OR^(a), —C(═O)R^(a),—C(═O)N(R^(a))₂, —N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))C(═O)R^(a),—N(R^(a))S(═O)_(t)R^(a) (where t is 1 or 2), —N(R^(a))S(═O)_(t)N(R^(a))₂(where t is 1 or 2), —S(═O)_(t)R^(a) (where t is 1 or 2),—S(═O)_(t)N(R^(a))₂ (where t is 1 or 2), —PO₃(R^(a))₂, —OPO₃WY (where Wand Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodiumor potassium) or —OPO₃Z (where Z is calcium, magnesium or iron), whereineach R^(a) is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl,heteroaryl or heteroarylalkyl.

“Imino” refers to a ═N—R^(a) radical, wherein R^(a) is hydrogen, alkyl,heteroalkyl, cycloalkyl, cyano, aryl, heterocycloalkyl or heteroaryl.

“Isocyanato” refers to a —NCO radical.

“Isothiocyanato” refers to a —NCS radical.

“Mercaptyl” refers to an —S(alkyl) or —SH radical.

“Methylene” refers to a ═CH₂ radical.

“Hydroxy” refers to a —OH radical.

“Oxa” refers to a —O— radical.

“Oxo” refers to a ═O radical.

“Nitro” refers to a —NO₂ radical.

“Oxime” refers to a ═N(—OR) radical, where R is hydrogen or alkyl.

“Sulfinyl” refers to a —S(═O)R radical, where R is selected from thegroup consisting of alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl(bonded through a ring carbon) and heterocycloalkyl (bonded through aring carbon). In some embodiments, R is fluoroalkyl.

“Sulfoxyl” refers to a —S(═O)₂OH radical.

“Sulfonate” refers to a —S(═O)₂OR radical, where R is selected from thegroup consisting of alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl(bonded through a ring carbon) and heteroalkyl (bonded through a ringcarbon). The R group is optionally substituted by one or more of thesubstituents described for alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl, respectively.

“Thiocyanato” refers to a —CNS radical.

“Thioxo” refers to a ═S radical.

“Moiety” refers to a specific segment or functional group of a molecule.Chemical moieties are often recognized chemical entities embedded in orappended to a molecule.

“Substituted” means that the referenced group may be substituted withone or more additional group(s) individually and independently selectedfrom acyl, alkyl, alkylaryl, heteroalkyl, cycloalkyl, aralkl,heterocycloalkyl, aryl, carbohydrate, carbonate, heteroaryl, hydroxy,alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl,ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro,oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl,sulfonamide, sulfoxyl, sulfonate, urea, and amino, including mono- anddi-substituted amino groups and the protected derivatives thereof. Thesubstituents themselves may be substituted, for example, a cycloalkylsubstituent may have a halide substituted at one or more ring carbons,and the like. The protecting groups that may form the protectivederivatives of the above substituents are known to those of skill in theart and may be found in references such as Wuts, Greene's ProtectiveGroups in Organic Synthesis, 5^(th) Ed., Wiley, New York, N.Y., 2014.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and includesinstances where the event or circumstance occurs and instances in whichit does not. For example, “alkyl optionally substituted with”encompasses both “alkyl” and “alkyl” substituted with groups as definedherein. It will be understood by those skilled in the art, with respectto any group containing one or more substituents, that such groups arenot intended to introduce any substitution or substitution patternswhich would be deemed unacceptable by one of ordinary skill in the art.

Compounds of the present invention also include crystalline andamorphous forms of those compounds, pharmaceutically acceptable salts,and active metabolites of these compounds having the same type ofactivity, including, for example, polymorphs, pseudopolymorphs,solvates, hydrates, unsolvated polymorphs (including anhydrates),conformational polymorphs, and amorphous forms of the compounds, as wellas mixtures thereof. “Crystalline form,” “polymorph,” and “novel form”may be used interchangeably herein, and are meant to include allcrystalline and amorphous forms of the compound, including, for example,polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs(including anhydrates), conformational polymorphs, and amorphous forms,as well as mixtures thereof, unless a particular crystalline oramorphous form is referred to.

The compounds described herein may exhibit their natural isotopicabundance, or one or more of the atoms may be artificially enriched in aparticular isotope having the same atomic number, but an atomic mass ormass number different from the atomic mass or mass number predominantlyfound in nature. All isotopic variations of the compounds of the presentinvention, whether radioactive or not, are encompassed within the scopeof the present invention. For example, hydrogen has three naturallyoccurring isotopes, denoted ¹H (protium), ²H (deuterium), and ³H(tritium). Protium is the most abundant isotope in nature. Enriching fordeuterium may afford certain therapeutic advantages, such as increasedin vivo half-life and/or exposure, or may provide a compound useful forinvestigating in vivo routes of drug elimination and metabolism.Isotopically-enriched compounds may be prepared by conventionaltechniques well known to those skilled in the art or by processesanalogous to those described in the Schemes and Examples herein usingappropriate isotopically-enriched reagents and/or intermediates. SeePleiss and Voger, Synthesis and Applications of Isotopically LabeledCompounds, Vol. 7, Wiley, ISBN-10: 0471495018, published on Mar. 14,2001.

“Isomers” are different compounds that have the same molecular formula.“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space. “Enantiomers” are a pair of stereoisomers that arenon superimposable mirror images of each other. A 1:1 mixture of a pairof enantiomers is a “racemic” mixture. The term “(±)” is used todesignate a racemic mixture where appropriate. “Diastereoisomers” or“diastereomers” are stereoisomers that have at least two asymmetricatoms but are not mirror images of each other. The absolutestereochemistry is specified according to the Cahn-Ingold-Prelog R-Ssystem. When a compound is a pure enantiomer, the stereochemistry ateach chiral carbon can be specified by either R or S. Resolved compoundswhose absolute configuration is unknown can be designated (+) or (−)depending on the direction (dextro- or levorotatory) in which theyrotate plane polarized light at the wavelength of the sodium D line.Certain compounds described herein contain one or more asymmetriccenters and can thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that can be defined, in terms of absolutestereochemistry, as (R)- or (S)-. The present chemical entities,pharmaceutical compositions and methods are meant to include all suchpossible isomers, including racemic mixtures, optically pure forms,mixtures of diastereomers and intermediate mixtures. Optically active(R)- and (S)-isomers can be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. The opticalactivity of a compound can be analyzed via any suitable method,including but not limited to chiral chromatography and polarimetry, andthe degree of predominance of one stereoisomer over the other isomer canbe determined.

Chemical entities having carbon-carbon double bonds or carbon-nitrogendouble bonds may exist in Z- or E-form (or cis- or trans-form).Furthermore, some chemical entities may exist in various tautomericforms. Unless otherwise specified, chemical entities described hereinare intended to include all Z-, E- and tautomeric forms as well.

The term “enantiomeric excess,” as used herein, is the percent excess ofone enantiomer compared to that of the other enantiomer in a mixture,and can be calculated using the following equation: enantiomericexcess=((R−S)/(R+S))×100=%(R*)−/%(S*), wherein R and S are the number ofmoles of each enantiomer in the mixture, and R* and S* are therespective mole fractions of the enantiomers in the mixture. Forexample, for a mixture with 87% R enantiomer and 13% S enantiomer, theenantiomeric excess is 74%.

“Tautomers” are structurally distinct isomers that interconvert bytautomerization. “Tautomerization” is a form of isomerization andincludes prototropic or proton-shift tautomerization, which isconsidered a subset of acid-base chemistry. “Prototropictautomerization” or “proton-shift tautomerization” involves themigration of a proton accompanied by changes in bond order, often theinterchange of a single bond with an adjacent double bond. Wheretautomerization is possible (e.g., in solution), a chemical equilibriumof tautomers can be reached. An example of tautomerization is keto-enoltautomerization. A specific example of keto-enol tautomerization is theinterconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-onetautomers. Another example of tautomerization is phenol-ketotautomerization. A specific example of phenol-keto tautomerization isthe interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

“Protecting group” has the meaning conventionally associated with it inorganic synthesis, i.e. a group that selectively blocks one or morereactive sites in a multifunctional compound such that a chemicalreaction can be carried out selectively on another unprotected reactivesite and such that the group can readily be removed after the selectivereaction is complete. A variety of protecting groups are disclosed, forexample, in Wuts, Greene's Protective Groups in Organic Synthesis,5^(th) Ed., Wiley, New York, N.Y., 2014. For example, a hydroxyprotected form is where at least one of the hydroxy groups present in acompound is protected with a hydroxy protecting group. Likewise, aminesand other reactive groups may similarly be protected.

“Solvate” refers to a compound in physical association with one or moremolecules of a pharmaceutically acceptable solvent. It will beunderstood that the present chemical entities encompass the presentchemical entities and solvates of the compound, as well as mixturesthereof.

“Solvent,” “organic solvent,” and “inert solvent” each means a solventinert under the conditions of the reaction being described inconjunction therewith, including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, N-methylpyrrolidone (“NMP”), pyridine and the like. Unlessspecified to the contrary, the solvents used in the reactions describedherein are inert organic solvents. Unless specified to the contrary, foreach gram of the limiting reagent, one cc (or mL) of solvent constitutesa volume equivalent.

Isolation and purification of the chemical entities and intermediatesdescribed herein can be effected, if desired, by any suitable separationor purification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography orthick-layer chromatography, or a combination of these procedures.Specific illustrations of suitable separation and isolation procedurescan be had by reference to the examples hereinbelow. However, otherequivalent separation or isolation procedures can also be used.

When desired, the (R)- and (S)-isomers of the compounds of the presentinvention, if present, may be resolved by methods known to those skilledin the art, for example by formation of diastereoisomeric salts orcomplexes which may be separated, for example, by crystallization; viaformation of diasteroisomeric derivatives which may be separated, forexample, by crystallization, gas-liquid or liquid chromatography;selective reaction of one enantiomer with an enantiomer-specificreagent, for example enzymatic oxidation or reduction, followed byseparation of the modified and unmodified enantiomers; or gas-liquid orliquid chromatography in a chiral environment, for example on a chiralsupport, such as silica with a bound chiral ligand or in the presence ofa chiral solvent. Alternatively, a specific enantiomer may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer tothe other by asymmetric transformation.

The compounds described herein can be optionally contacted with apharmaceutically acceptable acid to form the corresponding acid additionsalts. Pharmaceutically acceptable forms of the compounds recited hereininclude pharmaceutically acceptable salts, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof. In certain embodiments, thecompounds described herein are in the form of pharmaceuticallyacceptable salts. In addition, if the compound described herein isobtained as an acid addition salt, the free base can be obtained bybasifying a solution of the acid salt. Conversely, if the product is afree base, an addition salt, particularly a pharmaceutically acceptableaddition salt, may be produced by dissolving the free base in a suitableorganic solvent and treating the solution with an acid, in accordancewith conventional procedures for preparing acid addition salts from basecompounds. Those skilled in the art will recognize various syntheticmethodologies that may be used to prepare non-toxic pharmaceuticallyacceptable addition salts.

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary from, for example, between 1% and 15% of the statednumber or numerical range.

Abbreviations used herein have their conventional meaning within thechemical and biological arts.

The following abbreviations and terms have the indicated meaningsthroughout:

DAST=Diethylaminosulfur trifluoride

DCM=Dichloromethane

MTBE=Methyl t-butyl ether

HATU═O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

NBS=N-Bromosuccinimide

NMP=N-Methyl-2-pyrrolidone

e.e. or ee=Enantiomeric excess

PPTS=Pyridinium p-toluenesulfonate

TLC=Thin Layer Chromatography

DMAP=4-Dimethylaminopyridine

DMF=N,N-Dimethylformamide

When stereochemistry is not specified, certain small molecules describedherein include, but are not limited to, when possible, their isomers,such as enantiomers and diastereomers, mixtures of enantiomers,including racemates, mixtures of diastereomers, and other mixturesthereof, to the extent they can be made by one of ordinary skill in theart by routine experimentation. In those situations, the singleenantiomers or diastereomers, i.e., optically active forms, can beobtained by asymmetric synthesis or by resolution of the racemates ormixtures of diastereomers. Resolution of the racemates or mixtures ofdiastereomers, if possible, can be accomplished, for example, byconventional methods such as crystallization in the presence of aresolving agent, or chromatography, using, for example, a chiralhigh-pressure liquid chromatography (HPLC) column. Furthermore, amixture of two enantiomers enriched in one of the two can be purified toprovide further optically enriched form of the major enantiomer byrecrystallization and/or trituration. In addition, such certain smallmolecules include Z- and E-forms (or cis- and trans-forms) of certainsmall molecules with carbon-carbon double bonds or carbon-nitrogendouble bonds. Where certain small molecules described herein exist invarious tautomeric forms, the term “certain small molecule” is intendedto include all tautomeric forms of the certain small molecule.

When “

” is drawn across a bond, it denotes where a bond disconnection orattachment occurs. For example, in the chemical structure shown below,

R^(a) is attached to the para position of a fluorophenyl ring through asingle bond. When R^(a) is phenyl, it can also be drawn as

The waved line “

” means a bond with undefined stereochemistry. For example,

represents a mixture of

When a bond is drawn across a ring, it means substitution at anon-specific ring atom or position. For example, in the structure shownbelow,

R^(b) may be attached to any one of the —CH₂— in the five-membered ring.

When a bold bond “

” appears two or more times in the same chemical structure, a mixture ofthe two cis isomers of the compound is described. For example,

represents a mixture of the two isomers

In one aspect, the present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is O, S, CHR⁷, NR⁸ or absent;

R¹ is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, acyl or cyano;

R² is nitro, carboxaldehyde, carboxyl, ester, amido, cyano, halo,sulfonyl, alkyl, alkenyl, alkynyl or heteroalkyl;

R³ is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl,amino, carboxaldehyde, carboxylic acid, oxime, ester, amido or acyl; orR² and R³ taken together form a cyclic moiety;

R⁴ is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl,sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;and

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy.

In one aspect, the present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(HR⁷)—, —N(R⁸)—, C₁-C₃alkylene, C₁-C₃ heteroalkylene, C₁-C₃ alkenylene or absent;

R¹ is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, acyl or cyano;

R² is nitro, carboxaldehyde, carboxyl, ester, amido, cyano, halo,sulfonyl, alkyl, alkenyl, alkynyl or heteroalkyl;

R³ is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl,amino, carboxaldehyde, carboxylic acid, oxime, ester, amido or acyl; orR² and R³ taken together form a cyclic moiety;

R⁴ is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl,sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;and

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy.

In some embodiments, for a compound of Formula I, R¹ is further selectedfrom alkyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,aryl, heteroaryl, acyl or cyano.

In some embodiments, R¹ is phenyl or monocyclic heteroaryl. In somefurther embodiments, R¹ is phenyl or pyridyl, optionally substitutedwith one or more substituents selected from the group consisting ofhalo, alkyl, alkoxy and cyano. In a further embodiment, thesubstituent(s) is selected from the group consisting of halo, C₁-C₄alkyl, C₁-C₄ alkoxy and cyano.

In some embodiments, R¹ is bicyclic heteroaryl. In a further embodiment,the bicyclic heteroaryl is substituted with one or more substituentsselected from the group consisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxyand cyano.

In some embodiments, R¹ is pyridyl N-oxide. In a further embodiment, thepyridyl N-oxide is substituted with one or more substituents selectedfrom the group consisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano.

In some embodiments, R¹ is

wherein the aryl ring may optionally be substituted with one or moresubstituents selected from the group consisting of cyano, halo, alkyland alkoxy. In a further embodiment, the substituent(s) is selected fromthe group consisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano.

In some embodiments, R¹ is

wherein W¹ is N or CR¹⁰, R⁹ is cyano, halo, alkyl or alkoxy, and R¹⁰ ishydrogen, cyano, halo, alkyl or alkoxy. In a further embodiment, R⁹ iscyano, halo, C₁-C₄ alkyl or C₁-C₄ alkoxy, and R¹⁰ is hydrogen, cyano,halo, C₁-C₄ alkyl or C₁-C₄ alkoxy.

In some embodiments, R¹ is selected from the group consisting of:

and the rings specified for R¹ may optionally be substituted with one ormore substituents described for aryl and heteroaryl. In a furtherembodiment, the substituent(s) is selected from the group consisting ofhalo, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano.

In some embodiments, R¹ is selected from the group consisting of:

and the rings specified for R¹ may optionally be substituted with one ormore substituents described for cycloalkyl. In a further embodiment, thesubstituent(s) is selected from the group consisting of halo, hydroxy,C₁-C₄ alkyl, C₁-C₄ alkoxy, cyano and oxo.

In some embodiments, R¹ is cycloalkyl. In other embodiments, R¹ isheterocycloalkyl. In a further embodiment, R¹ is C₃-C₆ cycloalkyl orC₃-C₆ heterocycloalkyl. In yet a further embodiment, R¹ is cyclobutyl.In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl mayoptionally be substituted with one or more substituents described forcycloalkyl or heterocycloalkyl. In a further embodiment, thesubstituent(s) is selected from the group consisting of halo, C₁-C₄alkyl, C₁-C₄ alkoxy and cyano. In another further embodiment, thesubstituent(s) is at least one fluoro.

In some embodiments, R¹ is acyl or cyano. In a further embodiment, R¹ isacetyl.

In some embodiments, R¹ is alkyl. In a further embodiment, the alkyl issubstituted with at least one substituent(s) selected from the groupconsisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano. In anotherfurther embodiment, the alkyl is substituted with at least one fluoro.In some embodiments, R¹ is heteroalkyl.

In some embodiments, R¹ is selected from the group consisting of:

wherein each of the members may optionally be substituted with one ormore substituents selected from the group consisting of cyano, halo,alkyl and alkoxy. In a further embodiment, the substituent(s) isselected from the group consisting of fluoro, C₁-C₄ alkyl, C₁-C₄ alkoxyand cyano.

In some embodiments, R² is cyano, halo or alkyl. In some embodiments, R²is halo or alkyl. In some embodiments, R² is fluoro, chloro, bromo oriodo. In some embodiments, R² is fluoroalkyl. In some furtherembodiments, R² is —CH₂F, —CHF₂ or —CF₃. In another embodiment, R² ishydrogen. In some other embodiments, R² is heteroalkyl, alkenyl oralkynyl.

In some embodiments, R³ is hydrogen, halo, cyano, alkyl, alkenyl,heteroalkyl or acyl; or R² and R³ taken together form a cyclic moiety.In a further embodiment, R³ is halo, cyano or alkyl. In yet a furtherembodiment, R³ is —(CH₂)_(n)OH, wherein n is 1, 2 or 3. In still afurther embodiment, R³ is —CH₂OH.

In some embodiments, R² and R³ taken together with the atoms to whichthey are attached form a 5- or 6-membered carbocycle with at least onesp³ hybridized carbon. Representative compounds with the carbocycleinclude, but are not limited to, the following:

wherein the carbocycle formed by linking R² and R³ may be optionallysubstituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl. In afurther embodiment, the substituent(s) is selected from the groupconsisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano. In yet otherembodiments, the substituent(s) is cycloalkyl or heterocycloalkyl andshares one or more ring atoms with the carbocycle formed by linking R²and R³. In some embodiments, the substituent(s) is C₃-C₅ cycloalkyl orC₃-C₅ heterocycloalkyl. In other embodiments, the substituent is oxo.

In some embodiments, R² and R³ taken together with the atoms to whichthey are attached form a 5- or 6-membered heterocycle, including, butnot limited to, a lactone or lactol, wherein said heterocycle may beoptionally substituted with fluoro, chloro, hydroxy, alkyl orheteroalkyl. In a further embodiment, the substituent(s) is selectedfrom the group consisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano.

In some embodiments, R⁴ is halo, cyano, fluoroalkyl, sulfinyl,sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In someembodiments, R⁴ is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonylor sulfoximinyl. In some embodiments, R⁴ is fluoroalkyl, sulfonamidyl,sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In a further embodiment,R⁴ is fluoroalkyl. In yet another embodiment, R⁴ is sulfonyl. In stillanother embodiment, R⁴ is fluoroalkylsulfonyl.

In some embodiments, R⁴ is —S(═O)₂R^(a), wherein R^(a) is alkyl orcycloalkyl. In a further embodiment, R^(a) is C₁-C₄ alkyl, optionallysubstituted with one or more fluorines. Suitable examples offluorine-substituted C₁-C₄ alkyl include, but are not limited to, —CH₂F,—CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, —CHFCH₃ and —CF₂CH₃. In stilla further embodiment, R^(a) is methyl, optionally substituted with oneor more fluorines.

In some embodiments, R⁴ is —S(═O)(═NR^(b))R^(a), wherein R^(a) is alkylor cycloalkyl and R^(b) is hydrogen, cyano or alkyl. In a furtherembodiment, R^(a) is C₁-C₄ alkyl, optionally substituted with one ormore fluorines. Suitable examples of fluorine-substituted C₁-C₄ alkylinclude, but are not limited to, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂,—CH₂CH₂F, —CHFCH₃ and —CF₂CH₃.

In some embodiments, R⁴ is —S(═O)₂N(R^(a))₂, wherein each R^(a) isindependently hydrogen, alkyl, heteroalkyl, cycloalkyl orheterocycloalkyl, and at least one R^(a) is hydrogen. In a furtherembodiment, both R^(a)s are hydrogen. In another further embodiment, oneR^(a) is hydrogen and the other R^(a) is C₁-C₄ alkyl.

In some embodiments, R⁴ is selected from the group consisting of —CN,—CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃,—S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F,—S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F,—S(═O)(═N—CN)CHF₂ and —S(═O)(═N—CN)CF₃.

In some embodiments, R⁵ is hydrogen. In some other embodiments, R⁵ isC₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁵ is methyl.

In some embodiments, R⁶ is hydrogen. In some other embodiments, R⁶ isC₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁶ is methyl.

In some embodiments, R⁷ is hydrogen. In some other embodiments, R⁷ isC₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁷ is methyl.

In some embodiments, R⁸ is hydrogen. In some other embodiments, R⁸ isC₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁸ is methyl.

In some embodiments, R³ is hydrogen, R⁴ is —S(═O)₂R^(a) or—S(═O═NR^(b))R^(c), wherein R^(a) is fluoroalkyl, R^(b) is hydrogen,cyano or alkyl and R^(c) is alkyl. In a further embodiment, R¹ isselected from the group consisting of

wherein W¹ is N or CR¹⁰, R⁹ is cyano, halo, alkyl or alkoxy, and R¹⁰ ishydrogen, cyano, halo, alkyl or alkoxy; and

may optionally be substituted with one or more substituents selectedfrom the group consisting of cyano, halo, alkyl and alkoxy. In a furtherembodiment, the alkyl is C₁-C₄ alkyl. In another further embodiment, thealkoxy is C₁-C₄ alkoxy.

In some embodiments, each of R² and R³ is independently alkyl and R⁴ iscyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl orfluoroalkylsulfonyl.

In some embodiments, R³ is —CH₂OH. In a further embodiment, R⁴ is cyano,fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl orfluoroalkylsulfonyl and R⁵ is hydrogen. In still a further embodiment,R² is cyano, halo or alkyl.

In some embodiments, R¹ is phenyl or monocyclic heteroaryl; R² is nitro,halo, cyano or alkyl; R³ is halo, cyano or alkyl; R⁴ is cyano,fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl orfluoroalkylsulfonyl. In a further embodiment, R⁴ is selected from thegroup consisting of —CN, —CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F,—S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃,—S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃,—S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂ and —S(═O)(═N—CN)CF₃. In still afurther embodiment, R⁵ is hydrogen.

In some embodiments, R¹ is bicyclic heteroaryl; R² is nitro, halo, cyanoor alkyl; R³ is halo, cyano or alkyl; R⁴ is cyano, fluoroalkyl,sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;and R⁵ is hydrogen.

In some embodiments, R¹ is phenyl, monocyclic heteroaryl or bicyclicheteroaryl; R² is halo, cyano or alkyl; R³ is halo, cyano or alkyl; R⁴is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl orfluoroalkylsulfonyl; and R⁵ is hydrogen.

In some embodiments, R² and R³ together with the atoms to which they areattached form a 5- or 6-membered carbocycle with at least one sp³hybridized carbon; R⁴ is cyano, fluoroalkyl, sulfonamidyl, sulfinyl,sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; and R⁵ is hydrogen. In afurther embodiment, R¹ is phenyl or monocyclic heteroaryl. In anotherfurther embodiment, R¹ is bicyclic heteroaryl.

In some embodiments, X is N and Y is CR⁶. In other embodiments, X is CR⁵and Y is N. In still other embodiments, X is N and Y is N.

In some embodiments, Z is O. In other embodiments, Z is S. In furtherembodiments, Z is CHR⁷. In yet other embodiments, Z is NR⁸. In someembodiments, Z is absent.

In some embodiments, Z is —O—, —S—, —S(O)—, —S(O)₂—, —S(O₂)N(R⁸)—,—C(O)—, —C(O)O—, —C(HR⁷)—, —N(R⁸)—, —C(O)N(R⁸)—, alkylene, alkenylene,alkynylene, heteroalkylene, or absent. In some embodiments, Z is —O—,—S—, —S(O)—, —S(O)₂—, —C(O)—, —C(HR⁷)—, —N(R⁸)—, C₁-C₃ alkylene, C₁-C₃heteroalkylene, C₁-C₃ alkenylene or absent. In some embodiments, Z is—O—. In other embodiments, Z is —S—. In further embodiments, Z is—C(HR⁷)—. In yet other embodiments, Z is —N(R⁸). In some embodiments, Zis absent.

In another aspect, the invention provides a compound of Formula I-A:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is O, S, CHR⁷, NR⁸ or absent;

R² is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo,sulfonyl or alkyl;

R³ is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl,amino, oxime or acyl; or R² and R³ taken together form a cyclic moiety;

R⁴ is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl orsulfoximinyl;

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy;

W¹ is N or CR¹⁰;

R⁹ is cyano, halo, alkyl or alkoxy; and

R¹⁰ is hydrogen, cyano, halo, alkyl or alkoxy.

In another aspect, the invention provides a compound of Formula I-A:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(HR⁷)—, —N(R⁸)—, C₁-C₃alkylene, C₁-C₃ heteroalkylene, C₁-C₃ alkenylene or absent;

R² is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo,sulfonyl or alkyl;

R³ is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl,amino, oxime or acyl; or R² and R³ taken together form a cyclic moiety;

R⁴ is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl orsulfoximinyl;

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy;

W¹ is N or CR¹⁰;

R⁹ is cyano, halo, alkyl or alkoxy; and

R¹⁰ is hydrogen, cyano, halo, alkyl or alkoxy.

In some embodiments, R² is cyano, halo or alkyl. In some embodiments, R²is halo or alkyl. In some embodiments, R² is fluoro, chloro, bromo oriodo. In some embodiments, R² is fluoroalkyl. In some furtherembodiments, R² is —CH₂F, —CHF₂ or —CF₃.

In some embodiments, R³ is hydrogen, halo, cyano, alkyl, alkenyl,heteroalkyl or acyl; or R² and R³ taken together form a cyclic moiety.In a further embodiment, R³ is halo, cyano or alkyl. In yet a furtherembodiment, R³ is —(CH₂)_(n)OH, wherein n is 1, 2 or 3. In still afurther embodiment, R³ is —CH₂OH.

In some embodiments, R² and R³ taken together with the atoms to whichthey are attached form a 5- or 6-membered carbocycle with at least onesp³ hybridized carbon. Representative compounds with the carbocycleinclude, but are not limited to, the following:

wherein the carbocycle formed by linking R² and R³ may be optionallysubstituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl. In afurther embodiment, the substituent(s) is selected from the groupconsisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano. In yet otherembodiments, the substituent(s) is cycloalkyl or heterocycloalkyl andshares one or more ring atoms with the carbocycle formed by linking R²and R³. In some embodiments, the substituent(s) is C₃-C₅ cycloalkyl orC₃-C₅ heterocycloalkyl. In other embodiments, the substituent is oxo.

In some embodiments, R² and R³ taken together with the atoms to whichthey are attached form a 5- or 6-membered heterocycle, including, butnot limited to, a lactone or lactol, wherein said heterocycle may beoptionally substituted with fluoro, chloro, hydroxy, alkyl orheteroalkyl. In a further embodiment, the substituent(s) is selectedfrom the group consisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano.

In some embodiments, R⁴ is halo, cyano, fluoroalkyl, sulfinyl,sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In someembodiments, R⁴ is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonylor sulfoximinyl. In some embodiments, R⁴ is fluoroalkyl, sulfonamidyl,sulfonyl or sulfoximinyl. In a further embodiment, R⁴ is fluoroalkyl. Inyet another embodiment, R⁴ is sulfonyl. In still another embodiment, R⁴is fluoroalkylsulfonyl.

In some embodiments, R⁴ is —S(═O)₂R^(a), wherein R^(a) is alkyl orcycloalkyl. In a further embodiment, R^(a) is C₁-C₄ alkyl, optionallysubstituted with one or more fluorines. Suitable examples offluorine-substituted C₁-C₄ alkyl include, but are not limited to, —CH₂F,—CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, —CHFCH₃ and —CF₂CH₃. In stilla further embodiment, R^(a) is methyl, optionally substituted with oneor more fluorines.

In some embodiments, R⁴ is —S(═O)(═NR^(b))R^(a), wherein R^(a) is alkylor cycloalkyl and R^(b) is hydrogen, cyano or alkyl. In a furtherembodiment, R^(a) is C₁-C₄ alkyl, optionally substituted with one ormore fluorines. Suitable examples of fluorine-substituted C₁-C₄ alkylinclude, but are not limited to, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂,—CH₂CH₂F, —CHFCH₃ and —CF₂CH₃.

In some embodiments, R⁴ is —S(═O)₂N(R^(a))₂, wherein each R^(a) isindependently hydrogen, alkyl, heteroalkyl, cycloalkyl orheterocycloalkyl, and at least one R^(a) is hydrogen. In a furtherembodiment, both R^(a)s are hydrogen. In another further embodiment, oneR^(a) is hydrogen and the other R^(a) is C₁-C₄ alkyl.

In some embodiments, R⁴ is selected from the group consisting of —CN,—CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃,—S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F,—S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F,—S(═O)(═N—CN)CHF₂ and —S(═O)(═N—CN)CF₃.

In some embodiments, R⁵ is hydrogen. In some other embodiments, R⁵ isC₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁵ is methyl.

In some embodiments, R⁶ is hydrogen. In some other embodiments, R⁶ isC₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁶ is methyl.

In some embodiments, R⁷ is hydrogen. In some other embodiments, R⁷ isC₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁷ is methyl.

In some embodiments, R⁸ is hydrogen. In some other embodiments, R⁸ isC₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁸ is methyl.

In some embodiments, R⁹ is cyano, halo, C₁-C₄ alkyl or C₁-C₄ alkoxy.

In some embodiments, R¹⁰ is hydrogen, cyano, halo, C₁-C₄ alkyl or C₁-C₄alkoxy.

In some embodiments, R² and R³ taken together with the atoms to whichthey are attached form a 5- or 6-membered carbocycle with at least onesp³ hybridized carbon and R⁴ is cyano, fluoroalkyl, sulfonamidyl,sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl.

In some embodiments, R³ is —CH₂OH and R⁴ is cyano, fluoroalkyl,sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, R⁵ ishydrogen. In still a further embodiment, R² is cyano, halo or alkyl.

In some embodiments, R² is halo, cyano or alkyl; R³ is CH₂OH; R⁴ iscyano, fluoroalkyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a furtherembodiment, R⁴ is selected from the group consisting of —CN, —CF₃,—S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂,—S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂,—S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂and —S(═O)(═N—CN)CF₃.

In some embodiments, X is N and Y is CR⁶. In other embodiments, X is CR⁵and Y is N. In still other embodiments, X is N and Y is N.

In some embodiments, Z is O. In other embodiments, Z is S. In furtherembodiments, Z is CHR⁷. In yet other embodiments, Z is NR⁸. In someembodiments, Z is absent.

In some embodiments, Z is —O—, —S—, —S(O)—, —S(O)₂—, —S(O₂)N(R⁸)—,—C(O)—, —C(O)O—, —C(HR⁷)—, —N(R⁸)—, —C(O)N(R⁸)—, alkylene, alkenylene,alkynylene, heteroalkylene, or absent. In some embodiments, Z is —O—,—S—, —S(O)—, —S(O)₂—, —C(O)—, —C(HR⁷)—, —N(R⁸)—, C₁-C₃ alkylene, C₁-C₃heteroalkylene, C₁-C₃ alkenylene or absent. In some embodiments, Z is—O—. In other embodiments, Z is —S—. In further embodiments, Z is—C(HR⁷)—. In yet other embodiments, Z is —N(R⁸). In some embodiments, Zis absent.

In another aspect, the invention provides a compound of Formula I-B:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is O, S, CHR⁷, NR⁸ or absent;

R² is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo,sulfonyl or alkyl;

R³ is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl,amino, oxime or acyl; or R² and R³ taken together form a cyclic moiety;

R⁴ is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl orsulfoximinyl;

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy;

R^(c) is hydrogen, cyano, halo, alkyl or alkoxy; and

n′ is 0, 1, 2, 3 or 4.

In another aspect, the invention provides a compound of Formula I-B:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(HR⁷)—, —N(R⁸)—, C₁-C₃alkylene, C₁-C₃ heteroalkylene, C₁-C₃ alkenylene or absent;

R² is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo,sulfonyl or alkyl;

R³ is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl,amino, oxime or acyl; or R² and R³ taken together form a cyclic moiety;

R⁴ is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl orsulfoximinyl;

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy;

R^(c) is hydrogen, cyano, halo, alkyl or alkoxy; and

n′ is 0, 1, 2, 3 or 4.

In some embodiments, R² is cyano, halo or alkyl. In some embodiments, R²is halo or alkyl. In some embodiments, R² is fluoro, chloro, bromo oriodo. In some embodiments, R² is fluoroalkyl. In some furtherembodiments, R² is —CH₂F, —CHF₂ or —CF₃.

In some embodiments, R³ is hydrogen, halo, cyano, alkyl, alkenyl,heteroalkyl or acyl; or R² and R³ taken together form a cyclic moiety.In a further embodiment, R³ is halo, cyano or alkyl. In yet a furtherembodiment, R³ is —(CH₂)_(n)OH, wherein n is 1, 2 or 3.

In some embodiments, R² and R³ taken together with the atoms to whichthey are attached form a 5- or 6-membered carbocycle with at least onesp³ hybridized carbon. Representative compounds with the carbocycleinclude, but are not limited to, the following:

wherein the carbocycle formed by linking R² and R³ may be optionallysubstituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl. In afurther embodiment, the substituent(s) is selected from the groupconsisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano. In yet otherembodiments, the substituent(s) is cycloalkyl or heterocycloalkyl andshares one or more ring atoms with the carbocycle formed by linking R²and R³. In some embodiments, the substituent(s) is C₃-C₅ cycloalkyl orC₃-C₅ heterocycloalkyl. In other embodiments, the substituent is oxo.

In some embodiments, R² and R³ taken together with the atoms to whichthey are attached form a 5- or 6-membered heterocycle, including, butnot limited to, a lactone or lactol, wherein said heterocycle may beoptionally substituted with fluoro, chloro, hydroxy, alkyl orheteroalkyl. In a further embodiment, the substituent(s) is selectedfrom the group consisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano.

In some embodiments, R³ is hydrogen, R⁴ is —S(═O)₂R^(a) or—S(═O)(═NR^(b))R^(d), wherein R^(a) is fluoroalkyl, R^(b) is hydrogen,cyano or alkyl and R^(d) is alkyl.

In some embodiments, R⁴ is halo, cyano, fluoroalkyl, sulfinyl,sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In someembodiments, R⁴ is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonylor sulfoximinyl. In some embodiments, R⁴ is fluoroalkyl, sulfonamidyl,sulfonyl or sulfoximinyl. In a further embodiment, R⁴ is fluoroalkyl. Inyet another embodiment, R⁴ is sulfonyl. In still another embodiment, R⁴is fluoroalkylsulfonyl.

In some embodiments, R⁴ is —S(═O)₂R^(a), wherein R^(a) is alkyl orcycloalkyl. In a further embodiment, R^(a) is C₁-C₄ alkyl, optionallysubstituted with one or more fluorines. Suitable examples offluorine-substituted C₁-C₄ alkyl include, but are not limited to, —CH₂F,—CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, —CHFCH₃ and —CF₂CH₃. In stilla further embodiment, R^(a) is methyl, optionally substituted with oneor more fluorines.

In some embodiments, R⁴ is —S(═O)(═NR^(b))R^(a), wherein R^(a) is alkylor cycloalkyl and R^(b) is hydrogen, cyano or alkyl. In a furtherembodiment, R^(a) is C₁-C₄ alkyl, optionally substituted with one ormore fluorines. Suitable examples of fluorine-substituted C₁-C₄ alkylinclude, but are not limited to, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂,—CH₂CH₂F, —CHFCH₃ and —CF₂CH₃.

In some embodiments, R⁴ is —S(═O)₂—N(R^(a))₂, wherein each R^(a) isindependently hydrogen, alkyl, heteroalkyl, cycloalkyl orheterocycloalkyl, and at least one R^(a) is hydrogen. In a furtherembodiment, both R^(a)s are hydrogen. In another further embodiment, oneR^(a) is hydrogen and the other R^(a) is C₁-C₄ alkyl.

In some embodiments, R⁴ is selected from the group consisting of —CN,—CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃,—S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F,—S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F,—S(═O)(═N—CN)CHF₂ and —S(═O)(═N—CN)CF₃.

In some embodiments, R⁵ is hydrogen. In some other embodiments, R⁵ isC₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁵ is methyl.

In some embodiments, R⁶ is hydrogen. In some other embodiments, R⁶ isC₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁶ is methyl.

In some embodiments, R⁷ is hydrogen. In some other embodiments, R⁷ isC₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁷ is methyl.

In some embodiments, R⁸ is hydrogen. In some other embodiments, R⁸ isC₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁸ is methyl.

In some embodiments, R² and R³ taken together with the atoms to whichthey are attached form a 5- or 6-membered carbocycle with at least onesp³ hybridized carbon and R⁴ is cyano, fluoroalkyl, sulfonamidyl,sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In a furtherembodiment, R⁴ is selected from the group consisting of —CN, —CF₃,—S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂,—S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂,—S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂and —S(═O)(═N—CN)CF₃.

In some embodiments, R³ is —CH₂OH and R⁴ is fluoroalkyl, sulfonamidyl,sulfonyl, sulfinyl or sulfoximinyl. In a further embodiment, R⁵ ishydrogen. In still a further embodiment, R² is cyano, halo or alkyl.

In some embodiments, R² is halo, cyano or alkyl; R³ is CH₂OH; R⁴ isfluoroalkyl, sulfonamidyl, sulfonyl, sulfinyl or sulfoximinyl. In afurther embodiment, R⁴ is selected from the group consisting of —CF₃,—S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂,—S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂,—S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂and —S(═O)(═N—CN)CF₃.

In some embodiments, X is N and Y is CR⁶. In other embodiments, X is CR⁵and Y is N. In still other embodiments, X is N and Y is N.

In some embodiments, Z is O. In other embodiments, Z is S. In furtherembodiments, Z is CHR⁷. In yet other embodiments, Z is NR⁸. In someembodiments, Z is absent.

In some embodiments, Z is —O—, —S—, —S(O)—, —S(O)₂—, —S(O₂)N(R⁸)—,—C(O)—, —C(O)O—, —C(HR⁷)—, —N(R⁸)—, —C(O)N(R⁸)—, alkylene, alkenylene,alkynylene, heteroalkylene, or absent. In some embodiments, Z is —O—,—S—, —S(O)—, —S(O)₂—, —C(O)—, —C(HR⁷)—, —N(R⁸)—, C₁-C₃ alkylene, C₁-C₃heteroalkylene, C₁-C₃ alkenylene or absent. In some embodiments, Z is—O—. In other embodiments, Z is —S—. In further embodiments, Z is—C(HR⁷)—. In yet other embodiments, Z is —N(R⁸). In some embodiments, Zis absent.

In some embodiments, R^(c) is cyano, halo, C₁-C₄ alkyl or C₁-C₄ alkoxy.

In yet another aspect, the invention provides a compound of Formula I-C:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is O, S, CHR⁷, NR⁸ or absent;

R¹ is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl;

R⁴ is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl,sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy;

R¹¹ is hydrogen, hydroxy, alkoxy or amino;

R¹² is hydrogen, alkyl, alkenyl or alkynyl; or R¹¹ and R¹² incombination form oxo or oxime;

each of R¹³ is independently selected from the group consisting ofhydrogen, fluoro, chloro, hydroxy, alkyl and heteroalkyl; or two R¹³sand the carbon atom(s) to which they are attached form a 3- to8-membered cycloalkyl or heterocycloalkyl moiety; and

n is 0, 1, 2, 3 or 4.

In yet another aspect, the invention provides a compound of Formula I-C:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(HR⁷)—, —N(R⁸)—, C₁-C₃alkylene, C₁-C₃ heteroalkylene, C₁-C₃ alkenylene or absent;

R¹ is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl;

R⁴ is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl,sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy;

R¹¹ is hydrogen, halo, hydroxy, alkoxy or amino;

R¹² is hydrogen, alkyl, alkenyl or alkynyl; or R¹¹ and R¹² incombination form ═O, ═CH₂ or ═N(OH);

each of R¹³ is independently selected from the group consisting ofhydrogen, fluoro, chloro, hydroxy, alkyl and heteroalkyl; and two R¹³sand the carbon atom(s) to which they are attached may form a 3- to8-membered cycloalkyl or heterocycloalkyl moiety; and

n is 0, 1, 2, 3 or 4.

In some embodiments, for a compound of Formula I-C, R¹ is furtherselected from alkyl, heteroalkyl, cycloalkyl, cycloalkenyl,heterocycloalkyl, aryl and heteroaryl.

In some embodiments, R¹ is phenyl or monocyclic heteroaryl. In somefurther embodiments, R¹ is phenyl or pyridyl, optionally substitutedwith one or more substituents selected from the group consisting ofhalo, alkyl, alkoxy and cyano. In a further embodiment, R¹ is

wherein the aryl ring is optionally substituted with one or moresubstituents selected from the group consisting of cyano, halo, alkyland alkoxy. In another further embodiment, R¹ is

wherein W¹ is N or CR¹⁰, R⁹ is cyano, halo, alkyl or alkoxy, and R¹⁰ ishydrogen, cyano, halo, alkyl or alkoxy.

In some embodiments, R¹ is bicyclic heteroaryl.

In some embodiments, R¹ is selected from the group consisting of:

and the rings specified for R¹ may optionally be substituted with one ormore substituents described for aryl and heteroaryl. In a furtherembodiment, the substituent(s) is selected from the group consisting ofhalo, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano.

In some embodiments, R¹ is selected from the group consisting of:

and the rings specified for R¹ may optionally be substituted with one ormore substituents described for cycloalkyl. In a further embodiment, thesubstituent(s) is selected from the group consisting of halo, hydroxy,C₁-C₄ alkyl, C₁-C₄ alkoxy, cyano and oxo.

In some embodiments, R¹ is cycloalkyl. In other embodiments, R¹ isheterocycloalkyl. In a further embodiment, R¹ is C₃-C₆ cycloalkyl orC₃-C₆ heterocycloalkyl. In yet a further embodiment, R¹ is cyclobutyl.In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl mayoptionally be substituted with one or more substituents described forcycloalkyl or heterocycloalkyl. In a further embodiment, thesubstituent(s) is selected from the group consisting of halo, C₁-C₄alkyl, C₁-C₄ alkoxy and cyano. In another further embodiment, thesubstituent(s) is at least one fluoro.

In some embodiments, R¹ is cycloalkyl. In other embodiments, R¹ isheterocycloalkyl. In a further embodiment, R¹ is C₃-C₆ cycloalkyl orC₃-C₆ heterocycloalkyl. In yet a further embodiment, R¹ is cyclobutyl.In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl mayoptionally be substituted with one or more substituents described forcycloalkyl or heterocycloalkyl. In a further embodiment, thesubstituent(s) is selected from the group consisting of halo, hydroxy,C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano. In another further embodiment, thesubstituent(s) is at least one fluoro. In some embodiments, R¹ issubstituted with one to six fluorines.

In some embodiments, R¹ is acyl or cyano. In a further embodiment, R¹ isacetyl.

In some embodiments, R¹ is alkyl. In a further embodiment, the alkyl issubstituted with at least one substituent(s) selected from the groupconsisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano. In anotherfurther embodiment, the alkyl is substituted with at least one fluoro.In some embodiments, R¹ is heteroalkyl.

In some embodiments, R¹ is selected from the group consisting of:

wherein each of the members may optionally be substituted with one ormore substituents selected from the group consisting of cyano, halo,alkyl and alkoxy. In a further embodiment, the substituent(s) isselected from the group consisting of fluoro, C₁-C₄ alkyl, C₁-C₄ alkoxyand cyano.

In some embodiments, R¹ is selected from:

In some embodiments, R⁴ is cyano, fluoroalkyl, sulfinyl, sulfonamidyl,sulfonyl, sulfoximinyl, or fluoroalkylsulfonyl.

In some embodiments, R⁴ is cyano, fluoroalkyl, sulfinyl, sulfonamidyl,sulfonyl or sulfoximinyl. In some embodiments, R⁴ is fluoroalkyl,sulfonamidyl, sulfinyl, sulfonyl or sulfoximinyl. In a furtherembodiment, R⁴ is fluoroalkyl. In yet another embodiment, R⁴ issulfonyl. In still another embodiment, R⁴ is fluoroalkylsulfonyl.

In some embodiments, R⁴ is —S(═O)₂R^(a), wherein R^(a) is alkyl orcycloalkyl. In a further embodiment, R^(a) is C₁-C₄ alkyl, optionallysubstituted with one or more fluorines. Suitable examples offluorine-substituted C₁-C₄ alkyl include, but are not limited to, —CH₂F,—CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, —CHFCH₃ and —CF₂CH₃. In stilla further embodiment, R^(a) is methyl, optionally substituted with oneor more fluorines.

In some embodiments, R⁴ is —S(═O)(═NR^(b))R^(a), wherein R^(a) is alkylor cycloalkyl and R^(b) is hydrogen, cyano or alkyl. In a furtherembodiment, R^(a) is C₁-C₄ alkyl, optionally substituted with one ormore fluorines. Suitable examples of fluorine-substituted C₁-C₄ alkylinclude, but are not limited to, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂,—CH₂CH₂F, —CHFCH₃ and —CF₂CH₃.

In some embodiments, R⁴ is —S(═O)₂N(R^(a))₂, wherein each R^(a) isindependently hydrogen, alkyl, heteroalkyl, cycloalkyl orheterocycloalkyl, and at least one R^(a) is hydrogen. In another furtherembodiment, one R^(a) is hydrogen and the other R^(a) is C₁-C₄ alkyl.

In some embodiments, R⁴ is selected from the group consisting of —CN,—CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃,—S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F,—S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F,—S(═O)(═N—CN)CHF₂ and —S(═O)(═N—CN)CF₃.

In some embodiments, R⁵ is hydrogen or alkyl. In some other embodiments,R⁵ is C₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁵ ismethyl.

In some embodiments, R⁶ is hydrogen or alkyl. In some other embodiments,R⁶ is C₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁶ ismethyl.

In some embodiments, R⁷ is hydrogen or alkyl. In some other embodiments,R⁷ is C₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁷ ismethyl.

In some embodiments, R⁸ is hydrogen or alkyl. In some other embodiments,R⁸ is C₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁸ ismethyl.

In some embodiments, R¹² is hydrogen, alkyl, alkenyl or alkynyl; or R¹¹and R¹² in combination form ═O or ═N(OH).

In some embodiments, R¹¹ is hydroxy or amino. In a further embodiment,R¹¹ is hydroxy. In another further embodiment, R¹¹ is amino.

In some embodiments, R¹² is hydrogen. In some other embodiments, R¹² isalkyl or alkenyl.

In some embodiments, R¹³ is fluoro. In a further embodiment, n is 1, 2or 3. In a further embodiment, two R¹³s in combination form oxo, oximeor methylene. In still further embodiments, two R¹³s and the carbonatom(s) to which they are attached form a 3- to 8-membered cycloalkyl orheterocycloalkyl moiety.

In some embodiments, R¹ is monocyclic aryl or monocyclic heteroaryl andR¹¹ is hydroxy or amino. In a further embodiment, R¹³ is fluoro. Instill a further embodiment, n is 1, 2 or 3.

In some embodiments, R¹ is phenyl or monocyclic heteroaryl, R¹¹ ishydroxy or amino, R¹³ is fluoro, n is 1, 2 or 3, and R⁵ is hydrogen.

In some embodiments, R¹ is bicyclic heteroaryl and R¹¹ is hydroxy oramino. In a further embodiment, R¹³ is fluoro. In still a furtherembodiment, n is 1, 2 or 3.

In some embodiments, R¹ is bicyclic heteroaryl, R¹¹ is hydroxy or amino,R¹³ is fluoro, n is 1, 2 or 3, and R⁵ is hydrogen.

In some embodiments, R⁴ is cyano, fluoroalkyl, sulfonamidyl, sulfinyl,sulfonyl, sulfoximinyl or fluoroalkylsulfonyl, and R¹¹ is hydroxy oramino. In a further embodiment, R¹² is hydrogen. In another furtherembodiment, R¹³ is fluoro. In still a further embodiment, n is 1, 2 or3.

In some embodiments, R⁴ is cyano, fluoroalkyl, sulfonamidyl, sulfinyl,sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; R¹¹ is hydroxy or amino;R¹³ is fluoro; n is 1, 2 or 3; and R⁵ is hydrogen. In a furtherembodiment, R¹² is hydrogen.

In some embodiments R¹¹ is hydroxy or amino and R¹² is hydrogen. In afurther embodiment, R¹³ is fluoro. In still a further embodiment, n is1, 2 or 3.

In some embodiments R¹¹ is hydroxy or amino, R¹² is hydrogen, R¹³ isfluoro, n is 1, 2 or 3, and R⁵ is hydrogen. In a further embodiment, R⁴is selected from the group consisting of —CN, —CF₃, —S(═O)CH₃,—S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂,—S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂,—S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂and —S(═O)(═N—CN)CF₃.

In some embodiments, R⁴ is fluoroalkyl; n is 0, 1, 2 or 3; Z is O; R¹¹is hydroxy; and R¹² is hydrogen.

In some embodiments, R⁴ is sulfonyl or fluoroalkylsulfonyl; n is 0, 1, 2or 3; Z is O; R¹¹ is hydroxy; and R¹² is hydrogen.

In some embodiments, X is N and Y is CR⁶. In other embodiments, X is CR⁵and Y is N. In still other embodiments, X is N and Y is N.

In some embodiments, Z is O. In other embodiments, Z is S. In furtherembodiments, Z is CHR⁷. In yet other embodiments, Z is NR⁸. In someembodiments, Z is absent.

In some embodiments, Z is —O—, —S—, —S(O)—, —S(O)₂—, —S(O₂)N(R⁸)—,—C(O)—, —C(O)O—, —C(HR⁷)—, —N(R⁸)—, —C(O)N(R⁸)—, alkylene, alkenylene,alkynylene, heteroalkylene, or absent. In some embodiments, Z is —O—,—S—, —S(O)—, —S(O)₂—, —C(O)—, —C(HR⁷)—, —N(R⁸)—, C₁-C₃ alkylene, C₁-C₃heteroalkylene, C₁-C₃ alkenylene or absent. In some embodiments, Z is—O—. In other embodiments, Z is —S—. In further embodiments, Z is—C(HR⁷)—. In yet other embodiments, Z is —N(R⁸). In some embodiments, Zis absent.

In still another aspect, the invention provides a compound of FormulaI-D, I-E, I-F or I-G:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is O, S, CHR⁷, NR⁸ or absent;

R¹ is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl;

R⁴ is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl,sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy; and

R¹¹ is hydrogen, hydroxy, alkoxy or amino.

In still another aspect, the invention provides a compound of FormulaI-D, I-E, I-F or I-G:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(HR⁷)—, —N(R⁸)—, C₁-C₃alkylene, C₁-C₃ heteroalkylene, C₁-C₃ alkenylene or absent;

R¹ is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl;

R⁴ is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl,sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy; and

R¹¹ is hydrogen, halo, hydroxy, alkoxy or amino.

In some embodiments, for a compound of Formula I-D, I-E, I-F, or I-G, R¹is further selected from alkyl, heteroalkyl, cycloalkyl, cycloalkenyl,heterocycloalkyl, aryl and heteroaryl.

In some embodiments, R¹ is monocyclic aryl or monocyclic heteroaryl. Insome further embodiments, R¹ is phenyl or pyridyl, optionallysubstituted with one or more substituents selected from the groupconsisting of halo, alkyl, alkoxy and cyano. In a further embodiment, R¹is

wherein the aryl ring is optionally substituted with one or moresubstituents selected from the group consisting of cyano, halo, alkyland alkoxy. In another further embodiment, R¹ is

wherein W¹ is N or CR¹⁰, R⁹ is cyano, halo, alkyl or alkoxy, and R¹⁰ ishydrogen, cyano, halo, alkyl or alkoxy.

In some embodiments, R¹ is bicyclic heteroaryl having at least one Natom.

In some embodiments, R¹ is selected from the group consisting of:

and the rings specified for R¹ may optionally be substituted with one ormore substituents described for aryl and heteroaryl. In a furtherembodiment, the substituent(s) is selected from the group consisting ofhalo, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano.

In some embodiments, R¹ is selected from the group consisting of:

and the rings specified for R¹ may optionally be substituted with one ormore substituents described for cycloalkyl. In a further embodiment, thesubstituent(s) is selected from the group consisting of halo, hydroxy,C₁-C₄ alkyl, C₁-C₄ alkoxy, cyano and oxo.

In some embodiments, R¹ is cycloalkyl. In other embodiments, R¹ isheterocycloalkyl. In a further embodiment, R¹ is C₃-C₆ cycloalkyl orC₃-C₆ heterocycloalkyl. In yet a further embodiment, R¹ is cyclobutyl.In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl mayoptionally be substituted with one or more substituents described forcycloalkyl or heterocycloalkyl. In a further embodiment, thesubstituent(s) is selected from the group consisting of halo, C₁-C₄alkyl, C₁-C₄ alkoxy and cyano. In another further embodiment, thesubstituent(s) is at least one fluoro.

In some embodiments, R¹ is acyl or cyano. In a further embodiment, R¹ isacetyl.

In some embodiments, R¹ is alkyl. In a further embodiment, the alkyl issubstituted with at least one substituent(s) selected from the groupconsisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano. In anotherfurther embodiment, the alkyl is substituted with at least one fluoro.In some embodiments, R¹ is heteroalkyl.

In some embodiments, R¹ is selected from the group consisting of:

wherein each of the members may optionally be substituted with one ormore substituents selected from the group consisting of cyano, halo,alkyl and alkoxy. In a further embodiment, the substituent(s) isselected from the group consisting of fluoro, C₁-C₄ alkyl, C₁-C₄ alkoxyand cyano.

In some embodiments, R⁴ is cyano, fluoroalkyl, sulfinyl, sulfonamidyl,sulfonyl or sulfoximinyl. In some embodiments, R⁴ is fluoroalkyl,sulfonamidyl, sulfinyl, sulfonyl or sulfoximinyl. In a furtherembodiment, R⁴ is fluoroalkyl. In yet another embodiment, R⁴ issulfonyl. In still another embodiment, R⁴ is fluoroalkylsulfonyl.

In some embodiments, R⁴ is —S(═O)₂R^(a), wherein R^(a) is alkyl orcycloalkyl. In a further embodiment, R^(a) is C₁-C₄ alkyl, optionallysubstituted with one or more fluorines. Suitable examples offluorine-substituted C₁-C₄ alkyl include, but are not limited to, —CH₂F,—CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, —CHFCH₃ and —CF₂CH₃.

In some embodiments, R⁴ is —S(═O)(═NR^(b))R^(a), wherein R^(a) is alkylor cycloalkyl and R^(b) is hydrogen, cyano or alkyl. In a furtherembodiment, R^(a) is C₁-C₄ alkyl, optionally substituted with one ormore fluorines. Suitable examples of fluorine-substituted C₁-C₄ alkylinclude, but are not limited to, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂,—CH₂CH₂F, —CHFCH₃ and —CF₂CH₃.

In some embodiments, R⁴ is —S(═O)₂N(R^(a))₂, wherein each R^(a) isindependently hydrogen, alkyl, heteroalkyl, cycloalkyl orheterocycloalkyl, and at least one R^(a) is hydrogen. In another furtherembodiment, both R^(a)s are hydrogen. In a further embodiment, one R^(a)is hydrogen and the other R^(a) is C₁-C₄ alkyl.

In some embodiments, R⁴ is selected from the group consisting of —CN,—CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃,—S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F,—S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F,—S(═O)(═N—CN)CHF₂ and —S(═O)(═N—CN)CF₃.

In some embodiments, R⁵ is hydrogen or alkyl. In some other embodiments,R⁵ is C₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁵ ismethyl.

In some embodiments, R⁶ is hydrogen or alkyl. In some other embodiments,R⁶ is C₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁶ ismethyl.

In some embodiments, R⁷ is hydrogen or alkyl. In some other embodiments,R⁷ is C₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁷ ismethyl.

In some embodiments, R⁸ is hydrogen or alkyl. In some other embodiments,R⁸ is C₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁸ ismethyl.

In some embodiments, R¹¹ is hydroxy. In another further embodiment, R¹¹is amino.

In some embodiments, R¹ is phenyl or monocyclic heteroaryl and R¹¹ ishydroxy or amino.

In some embodiments, R¹ is bicyclic heteroaryl and R¹¹ is hydroxy oramino. In a further embodiment, X is CR⁵ and R⁵ is hydrogen. In anotherfurther embodiment, R⁵ is alkyl. In still a further embodiment, R⁵ isC₁-C₄ alkyl.

In some embodiments R¹ is bicyclic heteroaryl and R⁴ is cyano,fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In afurther embodiment, X is CR⁵ and R⁵ is hydrogen. In another furtherembodiment, R⁴ is selected from the group consisting of —CN, —CF₃,—S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂,—S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂,—S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂and —S(═O)(═N—CN)CF₃.

In some embodiments R¹ is bicyclic heteroaryl; R⁴ is cyano, fluoroalkyl,sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R¹¹ is hydroxy oramino; and X is CR⁵ or N; and R⁵ is hydrogen. In a further embodiment,R¹¹ is hydroxy. In another further embodiment, R⁴ is selected from thegroup consisting of —CN, —CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F,—S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃,—S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃,—S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂ and —S(═O)(═N—CN)CF₃.

In some embodiments R¹ is phenyl or monocyclic heteroaryl and R⁴ iscyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. Ina further embodiment, X is CR⁵ and R⁵ is hydrogen. In another furtherembodiment, R⁴ is selected from the group consisting of —CN, —CF₃,—S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂,—S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂,—S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂and —S(═O)(═N—CN)CF₃.

In some embodiments R¹ is phenyl or monocyclic heteroaryl; R⁴ is cyano,fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R¹¹ ishydroxy or amino; and X is CR⁵ or N; and R⁵ is hydrogen. In a furtherembodiment, R¹¹ is hydroxy. In another further embodiment, R⁴ isselected from the group consisting of —CN, —CF₃, —S(═O)CH₃, —S(═O)₂CH₃,—S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃,—S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃,—S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂ and—S(═O)(═N—CN)CF₃.

In some embodiments, X is N and Y is CR⁶. In other embodiments, X is CR⁵and Y is N. In still other embodiments, X is N and Y is N.

In some embodiments, Z is O. In other embodiments, Z is S. In furtherembodiments, Z is CHR⁷. In yet other embodiments, Z is NR⁸. In someembodiments, Z is absent.

In some embodiments, Z is —O—, —S—, —S(O)—, —S(O)₂—, —S(O₂)N(R⁸)—,—C(O)—, —C(O)O—, —C(HR⁷)—, —N(R⁸)—, —C(O)N(R⁸)—, alkylene, alkenylene,alkynylene, heteroalkylene, or absent. In some embodiments, Z is —O—,—S—, —S(O)—, —S(O)₂—, —C(O)—, —C(HR⁷)—, —N(R⁸)—, C₁-C₃ alkylene, C₁-C₃heteroalkylene, C₁-C₃ alkenylene or absent. In some embodiments, Z is—O—. In other embodiments, Z is —S—. In further embodiments, Z is—C(HR⁷)—. In yet other embodiments, Z is —N(R⁸). In some embodiments, Zis absent.

In a further aspect, the invention provides a compound of Formula I-H,I-I, I-J or I-K:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is O, S, CHR⁷, NR⁸ or absent;

R¹ is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl;

R⁴ is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl,sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy; and

R¹¹ is hydroxy or amino.

In a further aspect, the invention provides a compound of Formula I-H,I-I, I-J or I-K:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is CR⁵ or N;

Y is CR⁶ or N, wherein at least one of X and Y is N;

Z is —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(HR⁷)—, —N(R⁸)—, C₁-C₃alkylene, C₁-C₃ heteroalkylene, C₁-C₃ alkenylene or absent;

R¹ is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl;

R⁴ is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl,sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;

R⁵, R⁶, R⁷ and R⁸ are independently hydrogen, halo, hydroxy, cyano,alkyl or alkoxy; and

R¹¹ is hydrogen, halo, hydroxy, alkoxy or amino.

In some embodiments, for a compound of Formula I-H, I-I, I-J, or I-K, R¹is further selected from alkyl, heteroalkyl, cycloalkyl, cycloalkenyl,heterocycloalkyl, aryl and heteroaryl.

In some embodiments, R¹ is monocyclic aryl or monocyclic heteroaryl. Insome further embodiments, R¹ is phenyl or pyridyl, optionallysubstituted with one or more substituents selected from the groupconsisting of halo, alkyl, alkoxy and cyano. In a further embodiment, R¹is

wherein the aryl ring is optionally substituted with one or moresubstituents selected from the group consisting of cyano, halo, alkyland alkoxy. In another further embodiment, R¹ is

wherein W¹ is N or CR¹⁰, R⁹ is cyano, halo, alkyl or alkoxy, and R¹⁰ ishydrogen, cyano, halo, alkyl or alkoxy.

In some embodiments, R¹ is bicyclic heteroaryl.

In some embodiments, R¹ is selected from the group consisting of:

and the rings specified for R¹ may optionally be substituted with one ormore substituents described for aryl and heteroaryl. In a furtherembodiment, the substituent(s) is selected from the group consisting ofhalo, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano.

In some embodiments, R¹ is selected from the group consisting of:

and the rings specified for R¹ may optionally be substituted with one ormore substituents described for cycloalkyl. In a further embodiment, thesubstituent(s) is selected from the group consisting of halo, hydroxy,C₁-C₄ alkyl, C₁-C₄ alkoxy, cyano and oxo.

In some embodiments, R¹ is cycloalkyl. In other embodiments, R¹ isheterocycloalkyl. In a further embodiment, R¹ is C₃-C₆ cycloalkyl orC₃-C₆ heterocycloalkyl. In yet a further embodiment, R¹ is cyclobutyl.In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl mayoptionally be substituted with one or more substituents described forcycloalkyl or heterocycloalkyl. In a further embodiment, thesubstituent(s) is selected from the group consisting of halo, C₁-C₄alkyl, C₁-C₄ alkoxy and cyano. In another further embodiment, thesubstituent(s) is at least one fluoro.

In some embodiments, R¹ is cycloalkyl. In other embodiments, R¹ isheterocycloalkyl. In a further embodiment, R¹ is C₃-C₆ cycloalkyl orC₃-C₆ heterocycloalkyl. In yet a further embodiment, R¹ is cyclobutyl.In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl mayoptionally be substituted with one or more substituents described forcycloalkyl or heterocycloalkyl. In a further embodiment, thesubstituent(s) is selected from the group consisting of halo, hydroxy,C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano. In another further embodiment, thesubstituent(s) is at least one fluoro. In some embodiments, R¹ issubstituted with one to six fluorines.

In some embodiments, R¹ is acyl or cyano. In a further embodiment, R¹ isacetyl.

In some embodiments, R¹ is alkyl. In a further embodiment, the alkyl issubstituted with at least one substituent(s) selected from the groupconsisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano. In anotherfurther embodiment, the alkyl is substituted with at least one fluoro.In some embodiments, R¹ is heteroalkyl.

In some embodiments, R¹ is alkyl. In a further embodiment, the alkyl issubstituted with at least one substituent(s) selected from the groupconsisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano. In anotherfurther embodiment, the alkyl is substituted with at least one fluoro.In some embodiments, R¹ is heteroalkyl.

In some embodiments, R¹ is selected from the group consisting of:

wherein each of the members may optionally be substituted with one ormore substituents selected from the group consisting of cyano, halo,alkyl and alkoxy. In a further embodiment, the substituent(s) isselected from the group consisting of fluoro, C₁-C₄ alkyl, C₁-C₄ alkoxyand cyano.

In some embodiments, R¹ is selected from:

In some embodiments, R⁴ is cyano, fluoroalkyl, sulfinyl, sulfonamidyl,sulfonyl, sulfoximinyl, or fluoroalkylsulfonyl.

In some embodiments, R⁴ is cyano, fluoroalkyl, sulfinyl, sulfonamidyl,sulfonyl or sulfoximinyl. In a further embodiment, R⁴ is fluoroalkyl. Inyet another embodiment, R⁴ is sulfonyl. In still another embodiment, R⁴is fluoroalkylsulfonyl.

In some embodiments, R⁴ is —S(═O)₂R^(a), wherein R^(a) is alkyl orcycloalkyl. In a further embodiment, R^(a) is C₁-C₄ alkyl, optionallysubstituted with one or more fluorines. Suitable examples offluorine-substituted C₁-C₄ alkyl include, but are not limited to, —CH₂F,—CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, —CHFCH₃ and —CF₂CH₃. In stilla further embodiment, R^(a) is methyl, optionally substituted with oneor more fluorines.

In some embodiments, R⁴ is —S(═O)(═NR^(b))R^(a), wherein R^(a) is alkylor cycloalkyl and R^(b) is hydrogen, cyano or alkyl. In a furtherembodiment, R^(a) is C₁-C₄ alkyl, optionally substituted with one ormore fluorines. Suitable examples of fluorine-substituted C₁-C₄ alkylinclude, but are not limited to, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂,—CH₂CH₂F, —CHFCH₃ and —CF₂CH₃.

In some embodiments, R⁴ is —S(═O)₂N(R^(a))₂, wherein each R^(a) isindependently hydrogen, alkyl, heteroalkyl, cycloalkyl orheterocycloalkyl, and at least one R^(a) is hydrogen. In another furtherembodiment, both R^(a)s are hydrogen. In a further embodiment, one R^(a)is hydrogen and the other R^(a) is C₁-C₄ alkyl.

In some embodiments, R⁴ is selected from the group consisting of —CN,—CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃,—S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F,—S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F,—S(═O)(═N—CN)CHF₂ and —S(═O)(═N—CN)CF₃.

In some embodiments, R⁵ is hydrogen or alkyl. In some other embodiments,R⁵ is C₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁵ ismethyl.

In some embodiments, R⁶ is hydrogen or alkyl. In some other embodiments,R⁶ is C₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁶ ismethyl.

In some embodiments, R⁷ is hydrogen or alkyl. In some other embodiments,R⁷ is C₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁷ ismethyl.

In some embodiments, R⁸ is hydrogen or alkyl. In some other embodiments,R⁸ is C₁-C₄ alkyl or C₁-C₄ alkoxy. In a further embodiment, R⁸ ismethyl.

In some embodiments, R¹¹ is hydroxy. In another further embodiment, R¹¹is amino.

In some embodiments, R¹ is phenyl or monocyclic heteroaryl and R¹¹ ishydroxy or amino.

In some embodiments, R¹ is bicyclic heteroaryl and R¹¹ is hydroxy oramino. In a further embodiment, X is CR⁵ and R⁵ is hydrogen. In anotherfurther embodiment, R⁵ is alkyl. In still a further embodiment, R⁵ isC₁-C₄ alkyl.

In some embodiments R¹ is bicyclic heteroaryl and R⁴ is cyano,fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In afurther embodiment, X is CR⁵ and R⁵ is hydrogen. In another furtherembodiment, R⁴ is selected from the group consisting of —CN, —CF₃,—S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂,—S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂,—S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂and —S(═O)(═N—CN)CF₃.

In some embodiments R¹ is bicyclic heteroaryl; R⁴ is cyano, fluoroalkyl,sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R¹¹ is hydroxy oramino; and X is CR⁵ or N; and R⁵ is hydrogen. In a further embodiment,R¹¹ is hydroxy. In another further embodiment, R⁴ is selected from thegroup consisting of —CN, —CF₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F,—S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)(═NH)CH₃,—S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃,—S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂ and —S(═O)(═N—CN)CF₃.

In some embodiments R¹ is phenyl or monocyclic heteroaryl and R⁴ iscyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. Ina further embodiment, X is CR⁵ and R⁵ is hydrogen. In another furtherembodiment, R⁴ is selected from the group consisting of —CN, —CF₃,—S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂,—S(═O)₂NHCH₃, —S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂,—S(═O)(═NH)CF₃, —S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂and —S(═O)(═N—CN)CF₃.

In some embodiments R¹ is phenyl or monocyclic heteroaryl; R⁴ is cyano,fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R¹¹ ishydroxy or amino; and X is CR⁵ or N; and R⁵ is hydrogen. In a furtherembodiment, R¹¹ is hydroxy. In another further embodiment, R⁴ isselected from the group consisting of —CN, —CF₃, —S(═O)CH₃, —S(═O)₂CH₃,—S(═O)₂CH₂F, —S(═O)₂CHF₂, —S(═O)₂CF₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃,—S(═O)(═NH)CH₃, —S(═O)(═NH)CH₂F, —S(═O)(═NH)CHF₂, —S(═O)(═NH)CF₃,—S(═O)(═N—CN)CH₃, —S(═O)(═N—CN)CH₂F, —S(═O)(═N—CN)CHF₂ and—S(═O)(═N—CN)CF₃.

In some embodiments, R⁴ is fluoroalkyl; Z is —O—; and R¹¹ is hydroxy. Insome embodiments, R⁴ is sulfonyl; Z is —O—; and R¹¹ is hydroxy. In someembodiments, R¹ is phenyl, pyridyl, cycloalkyl or heterocycloalkyl,substituted with at least one substituent selected from the groupconsisting of halo, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano.

In some embodiments, X is N and Y is CR⁶. In other embodiments, X is CR⁵and Y is N. In still other embodiments, X is N and Y is N.

In some embodiments, Z is O. In other embodiments, Z is S. In furtherembodiments, Z is CHR⁷. In yet other embodiments, Z is NR⁸. In someembodiments, Z is absent.

In some embodiments, Z is —O—, —S—, —S(O)—, —S(O)₂—, —S(O₂)N(R⁸)—,—C(O)—, —C(O)O—, —C(HR⁷)—, —N(R⁸)—, —C(O)N(R⁸)—, alkylene, alkenylene,alkynylene, heteroalkylene, or absent. In some embodiments, Z is —O—,—S—, —S(O)—, —S(O)₂—, —C(O)—, —C(HR⁷)—, —N(R⁸)—, C₁-C₃ alkylene, C₁-C₃heteroalkylene, C₁-C₃ alkenylene or absent. In some embodiments, Z is—O—. In other embodiments, Z is —S—. In further embodiments, Z is—C(HR⁷)—. In yet other embodiments, Z is —N(R⁸). In some embodiments, Zis absent.

In some embodiments, a compound of any one of Formulae I-H-I-K may havean enantiomeric excess of at least about 80%, at least about 81%, atleast about 82%, at least about 83%, at least about 84%, at least about85%, at least about 86%, at least about 87%, at least about 88%, atleast about 89%, at least about 90%, at least about 91%, at least about92%, at least about 93%, at least about 94%, at least about 95%, atleast about 96%, at least about 97%, at least about 98%, or even higher.In some embodiments, a compound of any one of Formulae I-H-I-K may havean enantiomeric excess of about 80%, about 81%, about 82%, about 83%,about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%,about 97%, about 98% or about 99%.

In some other embodiments, exemplary compounds may include, but are notlimited to, a compound or pharmaceutically acceptable salt or prodrugthereof, selected from the following:

In some other embodiments, exemplary compounds may include, but are notlimited to, a compound or pharmaceutically acceptable salt or prodrugthereof, selected from the following:

In another aspect, the present disclosure provides a compound orpharmaceutically acceptable salt or prodrug thereof, selected from thegroup consisting of the compounds given in Table 1.

The chemical entities described herein can be synthesized according toone or more illustrative schemes herein and/or techniques known in theart. Materials used herein are either commercially available or preparedby synthetic methods generally known in the art. These schemes are notlimited to the compounds listed in the examples or by any particularsubstituents, which are employed for illustrative purposes. Althoughvarious steps are described and depicted in Schemes 1-5, the steps insome cases may be performed in a different order than the order shown inSchemes 1-5. Various modifications to these synthetic reaction schemesmay be made and will be suggested to one skilled in the art havingreferred to the disclosure contained in this Application. Numberings orR groups in each scheme do not necessarily correspond to that of theclaims or other schemes or tables herein.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure, generally within a temperature range from−10° C. to 200° C. Further, except as otherwise specified, reactiontimes and conditions are intended to be approximate, e.g., taking placeat about atmospheric pressure within a temperature range of about −10°C. to about 110° C. over a period of about 1 to about 24 hours;reactions left to run overnight average a period of about 16 hours.

In general, compounds of the invention may be prepared by the followingreaction schemes:

In some embodiments, compounds of Formula 1-8a and 1-8b can be preparedaccording to Scheme 1. For example, pyridine 1-1 may be converted toalkylaryl derivative 1-2 in Step A, wherein R⁴ is, for example,trifluoromethyl. The ketone may be converted to protected enol ether1-3, then fluorinated to give fluoroketal 1-4. Treatment of a compoundof Formula 1-4 with a suitable hydroxide source gives a mixture ofphenols 1-5a and 1-5b. Suitable hydroxide sources include, but are notlimited to, sodium hydroxide and potassium hydroxide. Suitable solventsfor the reaction include, but are not limited to, DMSO, DMA, DMF andEtOH. The phenols can undergo an SNAr reaction with a suitable halide togive aryl ethers of Formulae 1-6a and 1-6b, which may be deprotected togive the resultant ketones. In some embodiments, a compound of Formula1-7 is reduced with a hydride source to give a racemic mixture. In otherembodiments, an asymmetric reduction is carried out, affording alcohols1-8a and 1-8b, separable by methods known to one skilled in the art,such as, for example, conventional column chromatography. For example,direct asymmetric reduction of ketones 1-7a and 1-7b may be accomplishedchemically or enzymatically (Step G). For a recent review on enzymaticreduction of ketones, see Moore, et al. Acc. Chem. Res. 40: 1412-1419,2007. Examples of chemical asymmetric reduction of ketones include, butare not limited to, Corey-Bakshi-Shibata (CBS) reduction, asymmetrichydrogenation and asymmetric transfer hydrogenation. In someembodiments, the asymmetric transfer hydrogenation is catalyzed byruthenium. For examples of methods and catalysts for ruthenium catalyzedtransfer hydrogenation, see U.S. Pat. Nos. 6,184,381 and 6,887,820.Exemplary catalysts for asymmetric transfer hydrogenation include, butare not limited to, the following (shown as the R, R configuration):

The asymmetric transfer hydrogenation may be carried out at or belowroom temperature. In some embodiments, the asymmetric transferhydrogenation is carried out at about 4° C. The alcohol product may havean enantiomeric excess of at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, oreven higher. It is well understood by one skilled in the art thatchanging the catalyst configuration will lead to a product with theopposite configuration.

Alternatively, a compound of Formula 1-8a may be prepared according toScheme 2. For example, conversion of a compound of Formula 2-1 to aphenol is followed by coupling to form an aryl ether and deprotection togive a ketone of Formula 1-7b as described above. Ketone 1-7b isconverted to silyl enol ether 2-5 using a suitable silyl protectinggroup, including, for example, tert-butyldimethylsilyl,triisopropylsilyl or diphenyl-t-butylsilyl. The resulting silyl enolether is fluorinated to give fluoroketone 1-7a, which undergoes anasymmetric reduction, such as asymmetric transfer hydrogenation asdescribed herein, to give chiral alcohol 1-8a.

A compound of Formula 3-9 can be prepared following the generalprocedure outlined in Scheme 3, wherein the aryl fluoride of a compoundof Formula 3-1 is displaced with an alkyl thiol to give 3-2. Formationof benzaldehyde 3-3 may be followed by, for example, a Wittig reaction,to give alkene 3-4, which is reduced to an alkane of Formula 3-5 undersuitable conditions. In some embodiments, a Dieckmann condensationreaction is followed by a decarboxylation to give ketone 3-6. Oxidationof a compound of Formula 3-6 to give a compound of Formula 3-7 may beaccomplished by a variety of methods known in the art, including, butnot limited to, RuCl₃ catalyzed oxidation in the presence of NaIO₄,oxidation with m-chloroperoxybenzoic acid (mCPBA) and oxidation withOxone®. Protection of the ketone, for example, as the cyclic ketal (3-8)is followed by the general procedures outlined in Scheme 2 to give acompound of Formula 3-9.

In some embodiments, a compound of Formula 4-7 can be prepared accordingto Scheme 4. Formation of a chloropyridine of Formula 4-2 may befollowed by a nucleophilic aromatic substitution (SNAr) reaction with asuitable substrate of formula R¹OH to give a compound of Formula 4-3.Temperatures for carrying out the SNAr reaction may depend on thereactivity of both R¹OH and/or compound 4-2. The reaction may be carriedout at a temperature range from about room temperature to 200° C. Insome embodiments, the temperature range is from room temperature to 60°C. In some other embodiments, the temperature range is from 60° C. to100° C. In some other embodiments, the temperature range is from 100° C.to 200° C. Aryl bromide 4-3 may undergo a transition-metal catalyzedcoupling reaction with a thioate to give a compound of Formula 4-4.Hydrolysis, alkylation with a suitable alkyl halide and oxidationaffords a compound of Formula 4-7.

In some embodiments, a ketone of Formula 5-1 may be reduced to give 5-2,optionally with high enantioselectivity using asymmetric transferhydrogenation or enzymatic reduction conditions as described herein. Acompound of Formula 5-2 and a suitable coupling partner, including, butnot limited to, a boronic acid of formula R¹B(OH)₂, may undergo acoupling reaction to give a compound of Formula 5-3.

In some other embodiments, a compound of a formula given in Table 1 issynthesized according to one of the general routes outlined in Schemes1-5, Examples 1-5 or by methods generally known in the art.

TABLE 1 Mass Character- No. Structure ization ¹H NMR Data 1

(M + H) 328 (400 MHz, CDCl₃): δ 8.04 (s, 1H), 5.46- 5.26 (m, 2H),4.89-4.79 (m, 1H), 3.36- 3.08 (m, 4H), 2.91-2.74 (m, 2H), 2.60 (dd, 1H)2

(M + H) 310 (400 MHz, CDCl₃): δ 7.98 (s, 1H), 5.59- 5.54 (m, 1H),4.88-4.79 (m, 1H), 3.24- 3.07 (m, 3H), 2.89 (dd, 1H), 2.89-2.74 (m, 2H),2.44-2.34 (m, 1H), 2.28-2.21 (m, 1H), 2.12-2.09 (m, 1H) 3

(M + H) 357 (400 MHz, CDCl₃): δ 8.33 (s, 1H), 7.22 (ddd, 1H), 7.10-7.08(m, 1H), 6.99 (dt, 1H), 5.54-5.46 (m, 1H), 5.46-5.28 (m, 1H), 3.26 (ddd,1H), 3.11 (ddd, 1H), 2.67 (dd, 1H) 4

(M + H) 367 (400 MHz, CDCl₃): δ 8.27 (s, 1H), 7.25 (ddd, 1H), 7.14 (m,1H), 7.03 (dt, 1H), 5.69 (dt, 1H), 5.53-5.36 (m, 1H), 4.24 (d, 1H), 3.34(s, 3H), 3.31-3.24 (m, 1H), 3.09 (ddd, 1H) 5

326/328 (M + H) 6

362 (M + H) (400 MHz, CDCl₃): δ 7.49 (s, 1H), 6.80- 6.71 (m, 3H), 6.19(t, 1H), 3.36 (t, 2H), 3.06 (t, 2H), 2.31-2.23 (m, 2H) 7

(M + H) 341 (400 MHz, CDCl₃): δ 8.65 (s, 1H), 7.53- 7.48 (m, 2H), 7.40(ddd, 1H), 5.56-5.48 (m, 1H), 5.35 (ddt, 1H), 3.41 (ddd, 1H), 3.21 (ddd,1H), 2.65 (dd, 1H) 8

339 (M + H) 9

302 (M + H) 10

284 (M + H) 11

338 (M + H) 12

338 (M + H) 13

333 (M + H) 14

310 (M + H) 15

340 (M + H) 16

405/407 (M + H) (400 MHz, CDCl₃): δ 8.38 (d, 1H), 7.37- 7.36 (m, 1H),7.30 (ddd, 1H), 7.24 (dt, 1H), 6.09 (dddd, 1H), 6.00 (dddd, 1H) 17

403/405 (M + H) (400 MHz, CDCl₃): δ 8.36 (d, 1H), 7.37- 7.35 (m, 1H),7.29 (ddd, 1H), 7.25 (dt, 1H), 5.86 (dd, 1H), 5.11 (ddd, 1H), 2.73 (d,1H) 18

385 (M + H) (400 MHz, CDCl₃): δ 8.75 (d, 1H), 7.39- 7.37 (m, 1H), 7.34(ddd, 1H), 7.29-7.25 (m, 1H), 6.25 (ddd, 1H), 5.94-5.87 (m, 1H), 5.44(ddd, 1H), 3.66-3.58 (m,1H), 3.29 (s, 3H) 19

367 (M + H) (400 MHz, CDCl₃): δ 8.60-8.59 (m, 1H), 7.35-7.33 (m, 1H),7.31 (ddd, 1H), 7.24 (dt, 1H), 5.63 (ddd, 1H), 5.51 (dtd, 1H), 3.76 (dd,1H), 3.47-3.35 (m, 1H), 3.31 (s, 3H), 3.29-3.15 (m, 1H) 20

403 (M + H) (400 MHz, CDCl₃): δ 8.80 (d, 1H), 7.40- 7.38 (m, 1H), 7.36(ddd, 1H), 7.28 (dt, 1H), 5.88 (dd, 1H), 5.66-5.60 (m, 1H), 3.52 (dd,1H), 3.28 (s, 3H) 21

403 (M + H) (400 MHz, CDCl₃): δ 8.77 (d, 1H), 7.39- 7.37 (m, 1H), 7.35(ddd, 1H), 7.27 (dt, 1H), 6.00 (dd, 1H), 5.83 (tdd, 1H), 3.97 (d, 1H),3.29 (s, 3H) 22

375 (M + H) (400 MHz, CDCl₃): δ 8.42 (s, 1H), 7.28 (ddd, 1H), 7.20-7.18(m, 1H), 7.09 (dt, 1H), 5.92 (dt, 1H), 5.53-5.46 (m, 1H), 5.19 (ddt,1H), 2.66 (ddd, 1H) 23

298 (M + H) 24

298 (M + H) 25

280 (M + H) 26

280 (M + H) 27

302 (M + H) 28

349 (M + H) (400 MHz, CDCl₃): δ 8.52-8.51 (m, 1H), 7.33 (ddd, 1H), 7.29(ddd, 1H), 7.23 (dt, 1H), 5.71-5.66 (m, 1H), 3.64 (d, 1H), 3.26-3.17 (m,1H), 3.22 (s, 3H), 2.99- 2.90 (ddd, 1H), 2.66-2.56 (m, 1H), 2.32- 2.22(m, 1H) 29

367 (M + H) (400 MHz, CDCl₃): δ 8.60-8.59 (m, 1H), 7.35-7.33 (m, 1H),7.31 (ddd, 1H), 7.24 (dt, 1H), 5.63 (ddd, 1H), 5.52 (dtd, 1H), 3.76 (dd,1H), 3.47-3.35 (m, 1H), 3.31 (s, 3H), 3.29-3.15 (m, 1H) 30

310 (M + H) 31

310 (M + H) 32

339 (M + H) (400 MHz, CDCl₃): δ 8.29-8.27 (m, 1lH), 7.34-7.32 (m, 1H),7.26 (ddd, 1H), 7.22 (dt, 1H), 5.57-5.10 (m, 1H), 3.22 (dt, 1H), 2.96(ddd, 1H), 2.56-2.45 (m, 1H), 2.33-2.25 (m, 1H), 2.22-2.18 (m, 1H) 33

357 (M + H) (400 MHz, CDCl₃): δ 8.36-8.34 (m, 1H), 7.35-7.32 (m, 1H),7.28 (ddd, 1H), 7.23 (dt, 1H), 5.53-5.35 (m, 2H), 3.40 (ddd, 1H), 3.22(ddd, 1H), 2.73-2.68 (m, 1H) 34

358 (M + H) (400 MHz, CDCl₃): δ 8.79 (dd, 1H), 8.71 (d, 1H), 8.41 (s,1H), 7.67 (dd, 1H), 5.94 (dt, 1H), 5.53-5.46 (m, 1H), 5.21 (ddt, 1H),2.73 (ddd, 1H) 35

298 (M + H) (400 MHz, CDCl₃): δ 8.68 (s, 1H), 7.55- 7.45 (m, 3H),7.44-7.40 (m, 2H), 5.54- 5.46 (m, 1H), 5.31 (ddt, 1H), 3.46 (ddd, 1H),3.24 (ddd, 1H), 2.61 (dd, 1H) 36

334 (M + H) (400 MHz, CDCl₃): δ 8.65 (s, 1H), 6.99- 6.91 (m, 3H),5.54-5.47 (m, 1H), 5.33 (ddt, 1H), 3.44 (ddd, 1H), 3.23 (ddd, 1H), 2.63(dd, 1H) 37

346 (M + H) (400 MHz, CDCl₃): δ 8.24 (s, 1H), 5.95 (ddd, 1H), 5.47-5.41(m, 1H), 5.07 (ddt, 1H), 4.97-4.88 (m, 1H), 3.30-3.15 (m, 2H), 2.99-2.79(m, 2H), 2.54-2.49 (m, 1H) 38

315 (M + H) (400 MHz, DMSO-d₆): δ 8.30 (s, 1H), 6.26 (tt, 1H), 6.15(ddd, 1H), 4.55 (td, 2H), 3.46-3.32 (m, 1H), 3.13 (ddd, 1H) 39

324 (M + H) (400 MHz, CDCl₃): δ 8.14 (s, 1H), 6.10 (tt, 1H), 5.58-5.30(m, 1H), 4.39-4.24 (m, 2H), 3.10 (dt, 1H), 2.87 (ddd, 1H), 2.37- 2.27(m, 1H), 2.20-2.12 (m, 1H), 1.90- 1.86 (m, 1H), 1.47-1.39 (m, 2H), 1.27-1.21 (m, 2H) 40

351 (M + H) 41

351 (M + H) (400 MHz, CDCl₃): δ 8.75 (d, 1H), 8.65- 8.62 (m, 1H), 6.17(tt, 1H), 5.83 (dd, 1H), 4.83-4.64 (m, 2H) 42

340 (M + H) (400 MHz, CDCl₃): δ 7.43-7.41 (m, 1H), 7.33 (dt, 1H),7.33-7.29 (m, 1H), 5.67- 5.62 (m, 1H), 3.36-3.26 (m, 1H), 3.05 (ddd,1H), 2.63-2.53 (m, 1H), 2.40-2.30 (m, 2H)

Method of Use:

In one aspect, the present invention provides a method for treating aproliferative disorder in a subject in need thereof, comprisingadministering to said subject a HIF-2α inhibitor. In some embodiments,the proliferative disorder is a cancer condition. In some furtherembodiments, said cancer condition is a cancer selected from the groupconsisting of lung cancer, head and neck squamous cell carcinoma,pancreatic cancer, breast cancer, ovarian cancer, renal cell carcinoma,prostate cancer, neuroendocrine cancer, gastric cancer, bladder cancerand colon cancer. In another embodiment, the cancer condition is renalcell carcinoma.

In a further embodiment, the present invention provides a method oftreating a cancer condition, wherein the HIF-2α inhibitor is effectivein one or more of inhibiting proliferation of cancer cells, inhibitingmetastasis of cancer cells, killing cancer cells and reducing severityor incidence of symptoms associated with the presence of cancer cells.In some other embodiments, said method comprises administering to thecancer cells a therapeutically effective amount of a HIF-2α inhibitor.In some embodiments, the administration takes place in vitro. In otherembodiments, the administration takes place in vivo.

In some embodiments, the present invention provides a method of treatinga von Hippel-Lindau (VHL) disease, comprising administering to a subjectin need thereof an effective amount of a HIF-2α inhibitor describedherein. VHL disease is an autosomal dominant syndrome that not onlypredisposes patients to kidney cancer (˜70% lifetime risk), but also tohemangioblastomas, pheochromocytoma and pancreatic neuroendocrinetumors. VHL disease results in tumors with constitutively active HIF-αproteins with the majority of these dependent on HIF-2α activity (Maher,et al. Eur. J. Hum. Genet. 19: 617-623, 2011). HIF-2α has been linked tocancers of the retina, adrenal gland and pancreas through both VHLdisease and activating mutations. Recently, gain-of-function HIF-2αmutations have been identified in erythrocytosis and paraganglioma withpolycythemia (Zhuang, et al. NEJM 367: 922-930, 2012; Percy, et al. NEJM358: 162-168, 2008; and Percy, et al. Am. J. Hematol. 87: 439-442,2012). Notably, a number of known HIF-2α target gene products (e.g.,VEGF, PDGF, and cyclin D1) have been shown to play pivotal roles incancers derived from kidney, liver, colon, lung, and brain. In fact,therapies targeted against one of the key HIF-2α regulated geneproducts, VEGF, have been approved for the treatment of these cancers.

As used herein, a therapeutically effective amount of a HIF-2α inhibitorrefers to an amount sufficient to effect the intended application,including but not limited to, disease treatment, as defined herein. Alsocontemplated in the subject methods is the use of a sub-therapeuticamount of a HIF-2α inhibitor for treating an intended disease condition.

The amount of the HIF-2α inhibitor administered may vary depending uponthe intended application (in vitro or in vivo), or the subject anddisease condition being treated, e.g., the weight and age of thesubject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art.

Measuring inhibition of biological effects of HIF-2α can compriseperforming an assay on a biological sample, such as a sample from asubject. Any of a variety of samples may be selected, depending on theassay. Examples of samples include, but are not limited to blood samples(e.g. blood plasma or serum), exhaled breath condensate samples,bronchoalveolar lavage fluid, sputum samples, urine samples, and tissuesamples.

A subject being treated with a HIF-2α inhibitor may be monitored todetermine the effectiveness of treatment, and the treatment regimen maybe adjusted based on the subject's physiological response to treatment.For example, if inhibition of a biological effect of HIF-2α inhibitionis above or below a threshold, the dosing amount or frequency may bedecreased or increased, respectively. The methods can further comprisecontinuing the therapy if the therapy is determined to be efficacious.The methods can comprise maintaining, tapering, reducing, or stoppingthe administered amount of a compound in the therapy if the therapy isdetermined to be efficacious. The methods can comprise increasing theadministered amount of a compound in the therapy if it is determined notto be efficacious. Alternatively, the methods can comprise stoppingtherapy if it is determined not to be efficacious. In some embodiments,treatment with a HIF-2α inhibitor is discontinued if inhibition of thebiological effect is above or below a threshold, such as in a lack ofresponse or an adverse reaction. The biological effect may be a changein any of a variety of physiological indicators.

In general, a HIF-2α inhibitor is a compound that inhibits one or morebiological effects of HIF-2α. Examples of biological effects of HIF-2αinclude, but are not limited to, heterodimerization of HIF-2α to HIF-1β,HIF-2α target gene expression, VEGF gene expression, and VEGF proteinsecretion. In some embodiments, the HIF-2α inhibitor is selective forHIF-2α, such that the inhibitor inhibits heterodimerization of HIF-2α toHIF-1β but not heterodimerization of HIF-1α to HIF-1β. Such biologicaleffects may be inhibited by about or more than about 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, 95%, or more.

Hypoxia-inducible factors (HIFs), like HIF-2α, are transcription factorsthat respond to changes in available oxygen in the cellular environment(e.g. a decrease in oxygen, or hypoxia). The HIF signaling cascademediates the effects of hypoxia, the state of low oxygen concentration,on the cell. Hypoxia often keeps cells from differentiating. However,hypoxia promotes the formation of blood vessels, and is important forthe formation of a vascular system in embryos, and cancer tumors. Thehypoxia in wounds also promotes the migration of keratinocytes and therestoration of the epithelium. A HIF-2α inhibitor of the presentdisclosure may be administered in an amount effective in reducing anyone or more of such effects of HIF-2α activity.

HIF-2α activity can be inhibited by inhibiting heterodimerization ofHIF-2α to HIF-1β (ARNT), such as with inhibitor compounds disclosedherein. A variety of methods for measuring HIF-2α dimerization areavailable. In some embodiments, the HIF-2α inhibitor binds the PAS-Bdomain cavity of HIF-2α.

Inhibition of heterodimerization of HIF-2α to HIF-1β (ARNT) may also bedetermined by a reduction in HIF-2α target gene mRNA expression. mRNAquantitation can be performed using real-time PCR technology. (Wong, etal, “Real-time PCR for mRNA quantitation”, 2005. BioTechniques 39, 1:1-1.). Yet another method for determining inhibition ofheterodimerization of HIF-2α to HIF-1β (ARNT) is byco-immunoprecipitation.

As described herein, HIF-2α is a transcription factor that playsimportant roles in regulating expression of target genes. Non-limitingexamples of HIF-2α target genes include HMOX1, SFTPA1, CXCR4, PAI1,BDNF, hTERT, ATP7A, and VEGF. For instance, HIF-2α is an activator ofVEGF. Further non-limiting examples of HIF-2α target genes includeHMOX1, EPO, CXCR4, PAI1, CCND1, CLUT1, IL6, and VEGF. A HIF-2α inhibitorof the present disclosure may be administered in an amount effective inreducing expression of any one or more of genes induced by HIF-2αactivity. A variety of methods is available for the detection of geneexpression levels, and includes the detection of gene transcriptionproducts (polynucleotides) and translation products (polypeptides). Forexample, gene expression can be detected and quantified at the DNA, RNAor mRNA level. Various methods that have been used to quantify mRNAinclude in situ hybridization techniques, fluorescent in situhybridization techniques, reporter genes, RNase protection assays,Northern blotting, reverse transcription (RT)-PCR, SAGE, DNA microarray,tiling array, and RNA-seq. Examples of methods for the detection ofpolynucleotides include, but are not limited to selective colorimetricdetection of polynucleotides based on the distance-dependent opticalproperties of gold nanoparticles, and solution phase detection ofpolynucleotides using interacting fluorescent labels and competitivehybridization. Examples for the detection of proteins include, but arenot limited to microscopy and protein immunostaining, proteinimmunoprecipitation, immunoelectrophoresis, western blot, BCA assay,spectrophotometry, mass spectrophotometry and enzyme assay.

In some embodiments, inhibition of HIF-2α is characterized by a decreasein VEGF gene expression. The decrease may be measured by any of avariety of methods, such as those described herein. As a furtherexample, the mRNA expression level of VEGF can be measured byquantitative PCR (QT-PCR), microarray, RNA-seq and nanostring. Asanother example, an ELISA assay can be used to measure the level VEGFprotein secretion.

In some other embodiments, the subject methods are useful for treating adisease condition associated with HIF-2α. Any disease condition thatresults directly or indirectly from an abnormal activity or expressionlevel of HIF-2α can be an intended disease condition. In someembodiments, the disease condition is a proliferative disorder, such asdescribed herein, including but not limited to cancer. A role of HIF-2αin tumorigenesis and tumor progression has been implicated in many humancancers. Constitutively active HIF-2α may be the result of defective VHLor a low concentration of oxygen in a cancer cell. Rapidly growingtumors are normally hypoxic due to poor vascularization, a conditionthat activates HIF-2α in support of tumor cell survival andproliferation. Constitutive activation of HIF-2α is emerging as a commontheme in diverse human cancers, consequently agents that target HIF-2αhave therapeutic value.

The data presented in the Examples herein below demonstrate theanti-cancer effects of a HIF-2α inhibitor. As such, the subject methodis particularly useful for treating a proliferative disorder, such as aneoplastic condition. Non-limiting examples of such conditions includebut are not limited to acanthoma, acinic cell carcinoma, acousticneuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilicleukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia,acute monocytic leukemia, acute myeloblastic leukemia with maturation,acute myeloid dendritic cell leukemia, acute myeloid leukemia, acutepromyelocytic leukemia, adamantinoma, adenocarcinoma, adenoid cysticcarcinoma, adenoma, adenomatoid odontogenic tumor, adrenocorticalcarcinoma, adult T-cell leukemia, aggressive NK-cell leukemia,AIDS-related cancers, AIDS-related lymphoma, alveolar soft part sarcoma,ameloblastic fibroma, anal cancer, anaplastic large cell lymphoma,anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma,angiomyolipoma, angiosarcoma, appendix cancer, astrocytoma, atypicalteratoid rhabdoid tumor, basal cell carcinoma, basal-like carcinoma,B-cell leukemia, B-cell lymphoma, bellini duct carcinoma, biliary tractcancer, bladder cancer, blastoma, bone cancer, bone tumor, brain stemglioma, brain tumor, breast cancer, brenner tumor, bronchial tumor,bronchioloalveolar carcinoma, brown tumor, Burkitt's lymphoma, carcinoidtumor, carcinoma, carcinosarcoma, Castleman's disease, central nervoussystem embryonal tumor, cerebellar astrocytoma, cerebral astrocytoma,cervical cancer, cholangiocarcinoma, chondroma, chondrosarcoma,chordoma, choriocarcinoma, choroid plexus papilloma, chronic lymphocyticleukemia, chronic monocytic leukemia, chronic myelogenous leukemia,chronic myeloproliferative disorder, chronic neutrophilic leukemia,clear cell renal cell carcinoma, clear-cell tumor, colon cancer,colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma,dermatofibrosarcoma protuberans, dermoid cyst, desmoplastic small roundcell tumor, diffuse large B cell lymphoma, dysembryoplasticneuroepithelial tumor, embryonal carcinoma, endodermal sinus tumor,endometrial cancer, endometrial uterine cancer, endometrioid tumor,enteropathy-associated T-cell lymphoma, ependymoblastoma, ependymoma,epithelioid sarcoma, erythroleukemia,esophageal cancer,esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumor,extragonadal germ cell tumor, extrahepatic bile duct cancer,extramammary Paget's disease, fallopian tube cancer, fibroma,fibrosarcoma, follicular lymphoma, follicular thyroid cancer,gallbladder cancer, ganglioglioma, ganglioneuroma, gastric cancer,gastric lymphoma, gastrointestinal cancer, gastrointestinal carcinoidtumor, gastrointestinal stromal tumor, germ cell tumor, germinoma,gestational choriocarcinoma, gestational trophoblastic tumor, giant celltumor of bone, glioblastoma multiforme, glioma, gliomatosis cerebri,glomus tumor, glucagonoma, gonadoblastoma, granulosa cell tumor, hairycell leukemia, head and neck cancer, heart cancer, hemangioblastoma,hemangiopericytoma, hemangiosarcoma, hematological malignancy,hepatocellular carcinoma, hepatosplenic T-cell lymphoma, Hodgkinlymphoma, hypopharyngeal cancer, hypothalamic glioma, inflammatorybreast cancer, intraocular melanoma, islet cell carcinoma, juvenilemyelomonocytic leukemia, Kaposi's sarcoma, kidney cancer, klatskintumor, krukenberg tumor, laryngeal cancer, lentigo maligna melanoma,leukemia, lip and oral cavity cancer, liposarcoma, lung cancer, luteoma,lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoid leukemia,lymphoma, macroglobulinemia, malignant fibrous histiocytoma, malignantglioma, malignant mesothelioma, malignant peripheral nerve sheath tumor,malignant rhabdoid tumor, malignant triton tumor, malt lymphoma, mantlecell lymphoma, mast cell leukemia, mediastinal germ cell tumor,mediastinal tumor, medullary thyroid cancer, medulloblastoma,medulloepithelioma, melanoma, meningioma, merkel cell carcinoma,mesothelioma, metastatic squamous neck cancer with occult primary,metastatic urothelial carcinoma, mixed mullerian tumor, monocyticleukemia, mouth cancer, mucinous tumor, multiple endocrine neoplasiasyndrome, multiple myeloma, mycosis fungoides, myelodysplastic disease,myeloid leukemia, myeloid sarcoma, myeloproliferative disease, myxoma,nasal cavity cancer, nasopharyngeal cancer, neoplasm, neurinoma,neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-Hodgkinlymphoma, nonmelanoma skin cancer, non-small cell lung cancer, ocularoncology, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nervesheath meningioma, oral cancer, oropharyngeal cancer, osteosarcoma,ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor,ovarian low malignant potential tumor, pancoast tumor, pancreaticcancer, papillary thyroid cancer, papillomatosis, paraganglioma,paranasal sinus cancer, parathyroid cancer, penile cancer, perivascularepithelioid cell tumor, pharyngeal cancer, pheochromocytoma, pinealparenchymal tumor of intermediate differentiation, pineoblastoma,pituicytoma, pituitary adenoma, pituitary tumor, plasma cell neoplasm,pleuropulmonary blastoma, polyembryoma, precursor T-lymphoblasticlymphoma, primitive neuroectodermal tumor, prostate cancer, pseudomyxomaperitonei, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyoma, rhabdomyosarcoma, Richter's transformation, sacrococcygealteratoma, salivary gland cancer, sarcoma, schwannomatosis, sebaceousgland carcinoma, secondary neoplasm, seminoma, serous tumor,Sertoli-Leydig cell tumor, sex cord-stromal tumor, sezary syndrome,signet ring cell carcinoma, skin cancer, small blue round cell tumor,small cell carcinoma, small cell lung cancer, small cell lymphoma, smallintestine cancer, soft tissue sarcoma, somatostatinoma, soot wart,spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma,stomach cancer, superficial spreading melanoma, supratentorial primitiveneuroectodermal tumor, surface epithelial-stromal tumor, synovialsarcoma, T-cell acute lymphoblastic leukemia, T-cell large granularlymphocyte leukemia, T-cell leukemia, T-cell lymphoma, T-cellprolymphocytic leukemia, teratoma, terminal lymphatic cancer, testicularcancer, thecoma, throat cancer, thymic carcinoma, thymoma, thyroidcancer, transitional cell cancer of renal pelvis and ureter,transitional cell carcinoma, urachal cancer, urethral cancer, urogenitalneoplasm, uterine sarcoma, uveal melanoma, vaginal cancer, vernermorrison syndrome, verrucous carcinoma, visual pathway glioma, vulvarcancer, Waldenstrom's macroglobulinemia, Warthin's tumor, Wilms' tumoror any combination thereof.

In some embodiments, the methods of administering a HIF-2α inhibitordescribed herein are applied to the treatment of cancers of the adrenalglands, blood, bone marrow, brain, breast, cervix, colon, head and neck,kidney, liver, lung, ovary, pancreas, plasma cells, rectum, retina,skin, spine, throat or any combination thereof.

Certain embodiments contemplate a human subject such as a subject thathas been diagnosed as having or being at risk for developing oracquiring a proliferative disorder condition. Certain other embodimentscontemplate a non-human subject, for example a non-human primate such asa macaque, chimpanzee, gorilla, vervet, orangutan, baboon or othernon-human primate, including such non-human subjects that can be knownto the art as preclinical models. Certain other embodiments contemplatea non-human subject that is a mammal, for example, a mouse, rat, rabbit,pig, sheep, horse, bovine, goat, gerbil, hamster, guinea pig or othermammal. There are also contemplated other embodiments in which thesubject or biological source can be a non-mammalian vertebrate, forexample, another higher vertebrate, or an avian, amphibian or reptilianspecies, or another subject or biological source. In certain embodimentsof the present invention, a transgenic animal is utilized. A transgenicanimal is a non-human animal in which one or more of the cells of theanimal includes a nucleic acid that is non-endogenous (i.e.,heterologous) and is present as an extrachromosomal element in a portionof its cell or stably integrated into its germ line DNA (i.e., in thegenomic sequence of most or all of its cells).

Therapeutic Efficacy:

In some embodiments, therapeutic efficacy is measured based on an effectof treating a proliferative disorder, such as cancer. In general,therapeutic efficacy of the methods and compositions of the invention,with regard to the treatment of a proliferative disorder (e.g. cancer,whether benign or malignant), may be measured by the degree to which themethods and compositions promote inhibition of tumor cell proliferation,the inhibition of tumor vascularization, the eradication of tumor cells,the reduction in the rate of growth of a tumor, and/or a reduction inthe size of at least one tumor. Several parameters to be considered inthe determination of therapeutic efficacy are discussed herein. Theproper combination of parameters for a particular situation can beestablished by the clinician. The progress of the inventive method intreating cancer (e.g., reducing tumor size or eradicating cancerouscells) can be ascertained using any suitable method, such as thosemethods currently used in the clinic to track tumor size and cancerprogress. The primary efficacy parameter used to evaluate the treatmentof cancer by the inventive method and compositions preferably is areduction in the size of a tumor. Tumor size can be figured using anysuitable technique, such as measurement of dimensions, or estimation oftumor volume using available computer software, such as FreeFlightsoftware developed at Wake Forest University that enables accurateestimation of tumor volume. Tumor size can be determined by tumorvisualization using, for example, CT, ultrasound, SPECT, spiral CT, MRI,photographs, and the like. In embodiments where a tumor is surgicallyresected after completion of the therapeutic period, the presence oftumor tissue and tumor size can be determined by gross analysis of thetissue to be resected, and/or by pathological analysis of the resectedtissue.

In some desirable embodiments, the growth of a tumor is stabilized(i.e., one or more tumors do not increase more than 1%, 5%, 10%, 15%, or20% in size, and/or do not metastasize) as a result of the inventivemethod and compositions. In some embodiments, a tumor is stabilized forat least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more weeks. Insome embodiments, a tumor is stabilized for at least about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, or more months. In some embodiments, a tumoris stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or moreyears. Preferably, the inventive method reduces the size of a tumor atleast about 5% (e.g., at least about 10%, 15%, 20%, or 25%). Morepreferably, tumor size is reduced at least about 30% (e.g., at leastabout 35%, 40%, 45%, 50%, 55%, 60%, or 65%). Even more preferably, tumorsize is reduced at least about 70% (e.g., at least about 75%, 80%, 85%,90%, or 95%). Most preferably, the tumor is completely eliminated, orreduced below a level of detection. In some embodiments, a subjectremains tumor free (e.g. in remission) for at least about 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, or more weeks following treatment. In someembodiments, a subject remains tumor free for at least about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, or more months following treatment. In someembodiments, a subject remains tumor free for at least about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, or more years after treatment.

In some embodiments, the efficacy of the inventive method in reducingtumor size can be determined by measuring the percentage of necrotic(i.e., dead) tissue of a surgically resected tumor following completionof the therapeutic period. In some further embodiments, a treatment istherapeutically effective if the necrosis percentage of the resectedtissue is greater than about 20% (e.g., at least about 30%, 40%, 50%,60%, 70%, 80%, 90%, or 100%), more preferably about 90% or greater(e.g., about 90%, 95%, or 100%). Most preferably, the necrosispercentage of the resected tissue is 100%, that is, no tumor tissue ispresent or detectable.

The efficacy of the inventive method can be determined by a number ofsecondary parameters. Examples of secondary parameters include, but arenot limited to, detection of new tumors, detection of tumor antigens ormarkers (e.g., CEA, PSA, or CA-125), biopsy, surgical downstaging (i.e.,conversion of the surgical stage of a tumor from unresectable toresectable), PET scans, survival, disease progression-free survival,time to disease progression, quality of life assessments such as theClinical Benefit Response Assessment, and the like, all of which canpoint to the overall progression (or regression) of cancer in a human.Biopsy is particularly useful in detecting the eradication of cancerouscells within a tissue. Radioimmunodetection (RAID) is used to locate andstage tumors using serum levels of markers (antigens) produced by and/orassociated with tumors (“tumor markers” or “tumor-associated antigens”),and can be useful as a pre-treatment diagnostic predicate, apost-treatment diagnostic indicator of recurrence, and a post-treatmentindicator of therapeutic efficacy. Examples of tumor markers ortumor-associated antigens that can be evaluated as indicators oftherapeutic efficacy include, but are not limited to, carcinembryonicantigen (CEA), prostate-specific antigen (PSA), CA-125, CA19-9,ganglioside molecules (e.g., GM2, GD2, and GD3), MART-1, heat shockproteins (e.g., gp96), sialyl Tn (STn), tyrosinase, MUC-1, HER-2/neu,c-erb-B2, KSA, PSMA, p53, RAS, EGF-R, VEGF, MAGE, and gp100. Othertumor-associated antigens are known in the art. RAID technology incombination with endoscopic detection systems also can efficientlydistinguish small tumors from surrounding tissue (see, for example, U.S.Pat. No. 4,932,412).

In additional desirable embodiments, the treatment of cancer in a humanpatient in accordance with the inventive method is evidenced by one ormore of the following results: (a) the complete disappearance of a tumor(i.e., a complete response), (b) about a 25% to about a 50% reduction inthe size of a tumor for at least four weeks after completion of thetherapeutic period as compared to the size of the tumor beforetreatment, (c) at least about a 50% reduction in the size of a tumor forat least four weeks after completion of the therapeutic period ascompared to the size of the tumor before the therapeutic period, and (d)at least a 2% decrease (e.g., about a 5%, 10%, 20%, 30%, 40%, 50%, 60%,70%, 80% or 90% decrease) in a specific tumor-associated antigen levelat about 4-12 weeks after completion of the therapeutic period ascompared to the tumor-associated antigen level before the therapeuticperiod. While at least a 2% decrease in a tumor-associated antigen levelis preferred, any decrease in the tumor-associated antigen level isevidence of treatment of a cancer in a patient by the inventive method.For example, with respect to unresectable, locally advanced pancreaticcancer, treatment can be evidenced by at least a 10% decrease in theCA19-9 tumor-associated antigen level at 4-12 weeks after completion ofthe therapeutic period as compared to the CA19-9 level before thetherapeutic period. Similarly, with respect to locally advanced rectalcancer, treatment can be evidenced by at least a 10% decrease in the CEAtumor-associated antigen level at 4-12 weeks after completion of thetherapeutic period as compared to the CEA level before the therapeuticperiod.

With respect to quality of life assessments, such as the ClinicalBenefit Response Criteria, the therapeutic benefit of the treatment inaccordance with the invention can be evidenced in terms of painintensity, analgesic consumption, and/or the Karnofsky Performance Scalescore. The treatment of cancer in a human patient alternatively, or inaddition, is evidenced by (a) at least a 50% decrease (e.g., at least a60%, 70%, 80%, 90%, or 100% decrease) in pain intensity reported by apatient, such as for any consecutive four week period in the 12 weeksafter completion of treatment, as compared to the pain intensityreported by the patient before treatment, (b) at least a 50% decrease(e.g., at least a 60%, 70%, 80%, 90%, or 100% decrease) in analgesicconsumption reported by a patient, such as for any consecutive four weekperiod in the 12 weeks after completion of treatment as compared to theanalgesic consumption reported by the patient before treatment, and/or(c) at least a 20 point increase (e.g., at least a 30 point, 50 point,70 point, or 90 point increase) in the Karnofsky Performance Scale scorereported by a patient, such as for any consecutive four week period inthe 12 weeks after completion of the therapeutic period as compared tothe Karnofsky Performance Scale score reported by the patient before thetherapeutic period.

The treatment of a proliferative disorder (e.g. cancer, whether benignor malignant) in a human patient desirably is evidenced by one or more(in any combination) of the foregoing results, although alternative oradditional results of the referenced tests and/or other tests canevidence treatment efficacy.

In some embodiments, tumor size is reduced as a result of the inventivemethod preferably without significant adverse events in the subject.Adverse events are categorized or “graded” by the Cancer TherapyEvaluation Program (CTEP) of the National Cancer Institute (NCI), withGrade 0 representing minimal adverse side effects and Grade 4representing the most severe adverse events. Desirably, the inventivemethod is associated with minimal adverse events, e.g. Grade 0, Grade 1,or Grade 2 adverse events, as graded by the CTEP/NCI. However, asdiscussed herein, reduction of tumor size, although preferred, is notrequired in that the actual size of tumor may not shrink despite theeradication of tumor cells. Eradication of cancerous cells is sufficientto realize a therapeutic effect. Likewise, any reduction in tumor sizeis sufficient to realize a therapeutic effect.

Detection, monitoring and rating of various cancers in a human arefurther described in Cancer Facts and Figures 2001, American CancerSociety, New York, N.Y., and International Patent Application WO01/24684. Accordingly, a clinician can use standard tests to determinethe efficacy of the various embodiments of the inventive method intreating cancer. However, in addition to tumor size and spread, theclinician also may consider quality of life and survival of the patientin evaluating efficacy of treatment.

In some embodiments, administration of a HIF-2α inhibitor providesimproved therapeutic efficacy over treatment with either agent alone.Improved efficacy may be measured using any method known in the art,including but not limited to those described herein. In someembodiments, the improved therapeutic efficacy is an improvement of atleast about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 100%,110%, 120%, 150%, 200%, 300%, 400%, 500%, 600%, 700%, 1000% or more,using an appropriate measure (e.g. tumor size reduction, duration oftumor size stability, duration of time free from metastatic events,duration of disease-free survival). Improved efficacy may also beexpressed as fold improvement, such as at least about 2-fold, 3-fold,4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold,30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold,1000-fold, 10000-fold or more, using an appropriate measure (e.g. tumorsize reduction, duration of tumor size stability, duration of time freefrom metastatic events, duration of disease-free survival).

Pharmaceutical Compositions:

A composition of the present disclosure may be formulated in anysuitable pharmaceutical formulation. A pharmaceutical composition of thepresent disclosure typically contains an active ingredient (e.g., acompound of the present disclosure or a pharmaceutically acceptable saltand/or coordination complex thereof), and one or more pharmaceuticallyacceptable excipients, carriers, including but not limited to, inertsolid diluents and fillers, diluents, sterile aqueous solution andvarious organic solvents, permeation enhancers, solubilizers andadjuvants. A composition of the present disclosure may be formulated inany suitable pharmaceutical formulation. In some embodiments, thepharmaceutical acceptable carriers, excipients are selected from thegroup consisting of water, alcohol, glycerol, chitosan, alginate,chondroitin, Vitamin E, mineral oil, and dimethyl sulfoxide (DMSO).

Pharmaceutical formulations may be provided in any suitable form, whichmay depend on the route of administration. In some embodiments, thepharmaceutical composition disclosed herein can be formulated in dosageform for administration to a subject. In some embodiments, thepharmaceutical composition is formulated for oral, intravenous,intraarterial, aerosol, parenteral, buccal, topical, transdermal,rectal, intramuscular, subcutaneous, intraosseous, intranasal,intrapulmonary, transmucosal, inhalation, and/or intraperitonealadministration. In some embodiments, the dosage form is formulated fororal intervention administration. For example, the pharmaceuticalcomposition can be formulated in the form of a pill, a tablet, acapsule, an inhaler, a liquid suspension, a liquid emulsion, a gel, or apowder. In some embodiments, the pharmaceutical composition can beformulated as a unit dosage in liquid, gel, semi-liquid, semi-solid, orsolid form.

The amount of each compound administered will be dependent on the mammalbeing treated, the severity of the disorder or condition, the rate ofadministration, the disposition of the compound and the discretion ofthe prescribing physician. However, an effective dosage may be in therange of about 0.001 to about 100 mg per kg body weight per day, insingle or divided doses. In some instances, dosage levels below thelower limit of the aforesaid range may be more than adequate, while inother cases still larger doses may be employed without causing anyharmful side effect, e.g., by dividing such larger doses into severalsmall doses for administration throughout the day.

In some embodiments, the disclosure provides a pharmaceuticalcomposition comprising an amount of a HIF-2α inhibitor formulated foradministration to a subject in need thereof. In some embodiments, thepharmaceutical composition comprises between about 0.0001-500 g,0.001-250 g, 0.01-100 g, 0.1-50 g, or 1-10 g of HIF-2α inhibitor. Insome embodiments, the pharmaceutical composition comprises about or morethan about 0.0001 g, 0.001 g, 0.01 g, 0.1, 0.5 g, 1 g, 2 g, 3 g, 4 g, 5g, 6 g, 7 g, 8 g, 9 g, 10 g, 15 g, 20 g, 25 g, 50 g, 100 g, 200 g, 250g, 300 g, 350 g, 400 g, 450 g, 500 g, or more of a HIF-2α inhibitor. Insome embodiments, the pharmaceutical composition comprises between0.001-2 g of a HIF-2α inhibitor in a single dose. In some embodiments,the pharmaceutical composition comprises an amount between about 50-150g of a HIF-2α inhibitor. In some embodiments, the therapeutic amount canbe an amount between about 0.001-0.1 g of a HIF-2α inhibitor. In someembodiments, the therapeutic amount can be an amount between about0.01-30 g of a HIF-2α inhibitor.

In some embodiments, a therapeutically effective amount of HIF-2αinhibitor, which can be a daily amount administered over the course of aperiod of treatment, can sufficiently provide any one or more of thetherapeutic effects described herein. As an example, the therapeuticeffective amount can be in the range of about 0.001-1000 mg/kg bodyweight, 0.01-500 mg/kg body weight, 0.01-100 mg/kg body weight, 0.01-30mg/kg body weight, 0.1-200 mg/kg body weight, 3-200 mg/kg body weight,5-500 mg/kg body weight, 10-100 mg/kg body weight, 10-1000 mg/kg bodyweight, 50-200 mg/kg body weight, 100-1000 mg/kg body weight, 200-500mg/kg body weight, 250-350 mg/kg body weight, or 300-600 mg/kg bodyweight of a HIF-2α inhibitor. In some embodiments, the therapeuticamount can be about or more than about 0.001 mg/kg body weight, 0.01mg/kg body weight, 0.1 mg/kg body weight, 0.5 mg/kg body weight, 1 mg/kgbody weight, 2 mg/kg body weight, 3 mg/kg body weight, 4 mg/kg bodyweight, 5 mg/kg body weight, 6 mg/kg body weight, 7 mg/kg body weight, 8mg/kg body weight, 9 mg/kg body weight, 10 mg/kg body weight, 15 mg/kgbody weight, 20 mg/kg body weight, 25 mg/kg body weight, 50 mg/kg bodyweight, 100 mg/kg body weight, 200 mg/kg body weight, 250 mg/kg bodyweight, 300 mg/kg body weight, 350 mg/kg body weight, 400 mg/kg bodyweight, 450 mg/kg body weight, 500 mg/kg body weight, 600 mg/kg bodyweight, 800 mg/kg body weight, 1000 mg/kg body weight, or more of aHIF-2α inhibitor. In some embodiments, the effective amount is at leastabout 0.01 mg/kg body weight of a HIF-2α inhibitor. In some embodiments,the effective amount is an amount between about 0.01-30 mg/kg bodyweight of a HIF-2α inhibitor. In some embodiments, the therapeuticamount can be an amount between about 50-150 mg/kg body weight of aHIF-2α inhibitor.

In some embodiments, the composition is provided in one or more unitdoses. For example, the composition can be administered in 1, 2, 3, 4,5, 6, 7, 14, 30, 60, or more doses. Such amount can be administered eachday, for example in individual doses administered once, twice, or threeor more times a day. However, dosages stated herein on a per day basisshould not be construed to require administration of the daily dose eachand every day. For example, if one of the agents is provided in asuitably slow-release form, two or more daily dosage amounts can beadministered at a lower frequency, e.g., as a depot every second day toonce a month or even longer. Most typically and conveniently for thesubject, a HIF-2α inhibitor can be administered once a day, for examplein the morning, in the evening or during the day.

The unit doses can be administered simultaneously or sequentially. Thecomposition can be administered for an extended treatment period.Illustratively, the treatment period can be at least about one month,for example at least about 3 months, at least about 6 months or at leastabout 1 year. In some cases, administration can continue forsubstantially the remainder of the life of the subject.

In some embodiments, the HIF-2α inhibitor can be administered as part ofa therapeutic regimen that comprises administering one or more secondagents (e.g. 1, 2, 3, 4, 5, or more second agents), eithersimultaneously or sequentially with the HIF-2α inhibitor. Whenadministered sequentially, the HIF-2α inhibitor may be administeredbefore or after the one or more second agents. When administeredsimultaneously, the HIF-2α inhibitor and the one or more second agentsmay be administered by the same route (e.g. injections to the samelocation; tablets taken orally at the same time), by a different route(e.g. a tablet taken orally while receiving an intravenous infusion), oras part of the same combination (e.g. a solution comprising a HIF-2αinhibitor and one or more second agents).

A combination treatment according to the invention may be effective overa wide dosage range. For example, in the treatment of adult humans,dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg perday, and from 5 to 40 mg per day are examples of dosages that may beused. The exact dosage will depend upon the agent selected, the route ofadministration, the form in which the compound is administered, thesubject to be treated, the body weight of the subject to be treated, andthe preference and experience of the attending physician.

Pharmaceutical Composition for Oral Administration.

In some embodiments, the disclosure provides a pharmaceuticalcomposition for oral administration containing at least one compound ofthe present disclosure and a pharmaceutical excipient suitable for oraladministration. The composition may be in the form of a solid, liquid,gel, semi-liquid, or semi-solid. In some embodiments, the compositionfurther comprises a second agent.

In some embodiments, the invention provides a solid pharmaceuticalcomposition for oral administration containing: (i) a HIF-2α inhibitor;and (ii) a pharmaceutical excipient suitable for oral administration. Insome embodiments, the composition further contains: (iii) a third agentor even a fourth agent. In some embodiments, each compound or agent ispresent in a therapeutically effective amount. In other embodiments, oneor more compounds or agents is present in a sub-therapeutic amount, andthe compounds or agents act synergistically to provide a therapeuticallyeffective pharmaceutical composition.

Pharmaceutical compositions of the disclosure suitable for oraladministration can be presented as discrete dosage forms, such as hardor soft capsules, cachets, troches, lozenges, or tablets, or liquids oraerosol sprays each containing a predetermined amount of an activeingredient as a powder or in granules, a solution, or a suspension in anaqueous or non-aqueous liquid, an oil-in-water emulsion, or awater-in-oil liquid emulsion, or dispersible powders or granules, orsyrups or elixirs. Such dosage forms can be prepared by any of themethods of pharmacy, which typically include the step of bringing theactive ingredient(s) into association with the carrier. In general, thecomposition are prepared by uniformly and intimately admixing the activeingredient(s) with liquid carriers or finely divided solid carriers orboth, and then, if necessary, shaping the product into the desiredpresentation. For example, a tablet can be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets can be prepared by compressing in a suitable machine the activeingredient(s) in a free-flowing form such as powder or granules,optionally mixed with an excipient such as, but not limited to, abinder, a lubricant, an inert diluent, and/or a surface active ordispersing agent. Molded tablets can be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent.

This disclosure further encompasses anhydrous pharmaceutical compositionand dosage forms comprising an active ingredient, since water canfacilitate the degradation of some compounds. For example, water may beadded (e.g., 5%) in the pharmaceutical arts as a means of simulatinglong-term storage in order to determine characteristics such asshelf-life or the stability of formulations over time. Anhydrouspharmaceutical compositions and dosage forms of the disclosure can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. Pharmaceutical compositions anddosage forms of the disclosure which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition may be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous compositions maybe packaged using materials known to prevent exposure to water such thatthey can be included in suitable formulary kits. Examples of suitablepackaging include, but are not limited to, hermetically sealed foils,plastic or the like, unit dose containers, blister packs, and strippacks.

An active ingredient can be combined in an intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier can take a wide variety of formsdepending on the form of preparation desired for administration. Inpreparing the composition for an oral dosage form, any of the usualpharmaceutical media can be employed as carriers, such as, for example,water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents, and the like in the case of oral liquid preparations(such as suspensions, solutions, and elixirs) or aerosols; or carrierssuch as starches, sugars, micro-crystalline cellulose, diluents,granulating agents, lubricants, binders, and disintegrating agents canbe used in the case of oral solid preparations, in some embodimentswithout employing the use of lactose. For example, suitable carriersinclude powders, capsules, and tablets, with the solid oralpreparations. If desired, tablets can be coated by standard aqueous ornonaqueous techniques.

Binders suitable for use in pharmaceutical composition and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixturesthereof.

Examples of suitable fillers for use in the pharmaceutical compositionand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants may be used in the composition of the disclosure toprovide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant may produce tablets which maydisintegrate in the bottle. Too little may be insufficient fordisintegration to occur and may alter the rate and extent of release ofthe active ingredient(s) from the dosage form. A sufficient amount ofdisintegrant that is neither too little nor too much to detrimentallyalter the release of the active ingredient(s) may be used to form thedosage forms of the compounds disclosed herein. The amount ofdisintegrant used may vary based upon the type of formulation and modeof administration, and may be readily discernible to those of ordinaryskill in the art. About 0.5 to about 15 weight percent of disintegrant,or about 1 to about 5 weight percent of disintegrant, may be used in thepharmaceutical composition. Disintegrants that can be used to formpharmaceutical composition and dosage forms of the disclosure include,but are not limited to, agar-agar, alginic acid, calcium carbonate,microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate, potato or tapioca starch,other starches, pre-gelatinized starch, other starches, clays, otheralgins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical composition anddosage forms of the disclosure include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient therein may be combined withvarious sweetening or flavoring agents, coloring matter or dyes and, ifso desired, emulsifying and/or suspending agents, together with suchdiluents as water, ethanol, propylene glycol, glycerin and variouscombinations thereof.

The tablets can be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin or olive oil.

Surfactant which can be used to form pharmaceutical composition anddosage forms of the disclosure include, but are not limited to,hydrophilic surfactants, lipophilic surfactants, and mixtures thereof.That is, a mixture of hydrophilic surfactants may be employed, a mixtureof lipophilic surfactants may be employed, or a mixture of at least onehydrophilic surfactant and at least one lipophilic surfactant may beemployed.

A suitable hydrophilic surfactant may generally have an HLB value of atleast 10, while suitable lipophilic surfactants may generally have anHLB value of or less than about 10. An empirical parameter used tocharacterize the relative hydrophilicity and hydrophobicity of non-ionicamphiphilic compounds is the hydrophilic-lipophilic balance (“HLB”value). Surfactants with lower HLB values are more lipophilic orhydrophobic, and have greater solubility in oils, while surfactants withhigher HLB values are more hydrophilic, and have greater solubility inaqueous solutions. Hydrophilic surfactants are generally considered tobe those compounds having an HLB value greater than about 10, as well asanionic, cationic, or zwitterionic compounds for which the HLB scale isnot generally applicable. Similarly, lipophilic (i.e., hydrophobic)surfactants are compounds having an HLB value equal to or less thanabout 10. However, HLB value of a surfactant is merely a rough guidegenerally used to enable formulation of industrial, pharmaceutical andcosmetic emulsions.

Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts;fusidic acid salts; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acids,oligopeptides, and polypeptides; lecithins and hydrogenated lecithins;lysolecithins and hydrogenated lysolecithins; phospholipids andderivatives thereof; lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acylactylates; mono- and di-acetylated tartaricacid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof.

Within the aforementioned group, ionic surfactants include, by way ofexample: lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof; carnitine fatty acid ester salts; salts ofalkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides;succinylated mono- and di-glycerides; citric acid esters of mono- anddi-glycerides; and mixtures thereof.

Ionic surfactants may be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants may include, but not limited to,alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene glycol glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylenesterols, derivatives, and analogues thereof; polyoxyethylated vitaminsand derivatives thereof; polyoxyethylene-polyoxypropylene blockcopolymers; and mixtures thereof; polyethylene glycol sorbitan fattyacid esters and hydrophilic transesterification products of a polyolwith at least one member of the group consisting of triglycerides,vegetable oils, and hydrogenated vegetable oils. The polyol may beglycerol, ethylene glycol, polyethylene glycol, sorbitol, propyleneglycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate,sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octylphenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters; sorbitan fatty acid esters; polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives; polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides;hydrophobic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids and sterols; oil-solublevitamins/vitamin derivatives; and mixtures thereof. Within this group,preferred lipophilic surfactants include glycerol fatty acid esters,propylene glycol fatty acid esters, and mixtures thereof, or arehydrophobic transesterification products of a polyol with at least onemember of the group consisting of vegetable oils, hydrogenated vegetableoils, and triglycerides.

In one embodiment, the composition may include a solubilizer to ensuregood solubilization and/or dissolution of the compound of the presentdisclosure and to minimize precipitation of the compound of the presentdisclosure. This can be especially important for composition fornon-oral use, e.g., composition for injection. A solubilizer may also beadded to increase the solubility of the hydrophilic drug and/or othercomponents, such as surfactants, or to maintain the composition as astable or homogeneous solution or dispersion.

Examples of suitable solubilizers include, but are not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactoneand isomers thereof, β-butyrolactone and isomers thereof, and othersolubilizers known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, and water.

Mixtures of solubilizers may also be used. Examples include, but notlimited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. Particularlypreferred solubilizers include sorbitol, glycerol, triacetin, ethylalcohol, PEG-400, glycofurol and propylene glycol.

The amount of solubilizer that can be included is not particularlylimited. The amount of a given solubilizer may be limited to abioacceptable amount, which may be readily determined by one of skill inthe art. In some circumstances, it may be advantageous to includeamounts of solubilizers far in excess of bioacceptable amounts, forexample to maximize the concentration of the drug, with excesssolubilizer removed prior to providing the composition to a patientusing conventional techniques, such as distillation or evaporation. Ifpresent, the solubilizer can be in a weight ratio of 10%, 25%, 50%,100%, or up to about 200% by weight, based on the combined weight of thedrug, and other excipients. If desired, very small amounts ofsolubilizer may also be used, such as 5%, 2%, 1% or even less.Typically, the solubilizer may be present in an amount of about 1% toabout 100%, more typically about 5% to about 25% by weight.

The composition can further include one or more pharmaceuticallyacceptable additives and excipients. Such additives and excipientsinclude, without limitation, detackifiers, anti-foaming agents,buffering agents, polymers, antioxidants, preservatives, chelatingagents, viscomodulators, tonicifiers, flavorants, colorants, odorants,opacifiers, suspending agents, binders, fillers, plasticizers,lubricants, and mixtures thereof.

In addition, an acid or a base may be incorporated into the compositionto facilitate processing, to enhance stability, or for other reasons.Examples of pharmaceutically acceptable bases include amino acids, aminoacid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide,sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate,magnesium hydroxide, magnesium aluminum silicate, synthetic aluminumsilicate, synthetic hydrocalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamine, trimethylamine,tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable arebases that are salts of a pharmaceutically acceptable acid, such asacetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, amino acids, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, fatty acids, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionicacid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinicacid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonicacid, uric acid, and the like. Salts of polyprotic acids, such as sodiumphosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphatecan also be used. When the base is a salt, the cation can be anyconvenient and pharmaceutically acceptable cation, such as ammonium,alkali metals, alkaline earth metals, and the like. Example may include,but not limited to, sodium, potassium, lithium, magnesium, calcium andammonium.

Suitable acids are pharmaceutically acceptable organic or inorganicacids. Examples of suitable inorganic acids include hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boricacid, phosphoric acid, and the like. Examples of suitable organic acidsinclude acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid, uric acid and the like.

Pharmaceutical Composition for Topical (e.g., Transdermal) Delivery.

In some embodiments, the invention provides a pharmaceutical compositionfor transdermal delivery containing a compound of the present inventionand a pharmaceutical excipient suitable for transdermal delivery. Thecomposition may be in the form of a solid, liquid, gel, semi-liquid, orsemi-solid. In some embodiments, the composition further comprises asecond agent.

Composition of the present disclosure can be formulated intopreparations in solid, semi-solid, or liquid forms suitable for local ortopical administration, such as gels, water soluble jellies, creams,lotions, suspensions, foams, powders, slurries, ointments, solutions,oils, pastes, suppositories, sprays, emulsions, saline solutions,dimethylsulfoxide (DMSO)-based solutions. In general, carriers withhigher densities are capable of providing an area with a prolongedexposure to the active ingredients. In contrast, a solution formulationmay provide more immediate exposure of the active ingredient to thechosen area.

The pharmaceutical composition also may comprise suitable solid or gelphase carriers or excipients, which are compounds that allow increasedpenetration of, or assist in the delivery of, therapeutic moleculesacross the stratum corneum permeability barrier of the skin. There aremany of these penetration-enhancing molecules known to those trained inthe art of topical formulation. Examples of such carriers and excipientsinclude, but are not limited to, humectants (e.g., urea), glycols (e.g.,propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleicacid), surfactants (e.g., isopropyl myristate and sodium laurylsulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes(e.g., menthol), amines, amides, alkanes, alkanols, water, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as polyethylene glycols.

Formulations for topical administration may include ointments, lotions,creams, gels (e.g., poloxamer gel), drops, suppositories, sprays,liquids and powders. Conventional pharmaceutical carriers, aqueous,powder or oily bases, thickeners and the like may be necessary ordesirable. The disclosed compositions can be administered, for example,in a microfiber, polymer (e.g., collagen), nanosphere, aerosol, lotion,cream, fabric, plastic, tissue engineered scaffold, matrix material,tablet, implanted container, powder, oil, resin, wound dressing, bead,microbead, slow release bead, capsule, injectables, intravenous drips,pump device, silicone implants, or any bio-engineered materials.

Another exemplary formulation for use in the methods of the presentdisclosure employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of a compound of the present disclosure in controlled amounts,either with or without another agent.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art. See, e.g., U.S. Pat.Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents.

Pharmaceutical Composition for Injection.

In some embodiments, the disclosure provides a pharmaceuticalcomposition for injection containing a compound of the presentdisclosure and a pharmaceutical excipient suitable for injection.Components and amounts of agents in the composition are as describedherein.

The forms in which the novel composition of the present disclosure maybe incorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, andvegetable oils may also be employed. The proper fluidity can bemaintained, for example, by the use of a coating, such as lecithin, forthe maintenance of the required particle size in the case of dispersionand by the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the compoundof the present disclosure in the required amount in the appropriatesolvent with various other ingredients as enumerated above, as required,followed by filtered sterilization. Generally, dispersions are preparedby incorporating the various sterilized active ingredients into asterile vehicle which contains the basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions,certain desirable methods of preparation are vacuum-drying andfreeze-drying techniques which yield a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Pharmaceutical Composition for Inhalation.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid composition maycontain suitable pharmaceutically acceptable excipients as describedvide supra. Preferably, the compositions are administered by the oral ornasal respiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver the formulationin an appropriate manner.

Other Pharmaceutical Composition.

Pharmaceutical composition may also be prepared from compositiondescribed herein and one or more pharmaceutically acceptable excipientssuitable for sublingual, buccal, rectal, intraosseous, intraocular,intranasal, epidural, or intraspinal administration. Preparations forsuch pharmaceutical composition are well-known in the art. See, e.g.,See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G,eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002;Pratt and Taylor, eds., Principles of Drug Action, Third Edition,Churchill Livingston, N.Y., 1990; Katzung, ed., Basic and ClinicalPharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman,eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGrawHill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., LippincottWilliams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia,Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all ofwhich are incorporated by reference herein in their entirety.

The compounds of the present invention can also be administered in theform of liposomes. As is known in the art, liposomes are generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono- or multilamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and metabolizable lipid capable of forming liposomes can beused. The present compositions in liposome form can contain, in additionto a compound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natural and synthetic. Methodsto form liposomes are known in the art. See, for example, Prescott, Ed.,“Methods in Cell Biology”, Volume XIV, ISBN: 978-0-12-564114-2, AcademicPress, New York, N.W., p. 33 (1976) and Medina, Zhu, and Kairemo,“Targeted liposomal drug delivery in cancer”, Current Pharm. Des. 10:2981-2989, 2004. For additional information regarding drug formulationand administration, see “Remington: The Science and Practice ofPharmacy,” Lippincott Williams & Wilkins, Philadelphia, ISBN-10:0781746736, 21^(st) Edition (2005).

The invention also provides kits. The kits may include a HIF-2αinhibitor and one or more additional agents in suitable packaging withwritten material that can include instructions for use, discussion ofclinical studies, listing of side effects, and the like. Such kits mayalso include information, such as scientific literature references,package insert materials, clinical trial results, and/or summaries ofthese and the like, which indicate or establish the activities and/oradvantages of the composition, and/or which describe dosing,administration, side effects, drug interactions, or other informationuseful to the health care provider. Such information may be based on theresults of various studies, for example, studies using experimentalanimals involving in vivo models and studies based on human clinicaltrials. The kit may further contain another agent. In some embodiments,the compound of the present invention and the agent are provided asseparate compositions in separate containers within the kit. In someembodiments, the compound of the present invention and the agent areprovided as a single composition within a container in the kit. Suitablepackaging and additional articles for use (e.g., measuring cup forliquid preparations, foil wrapping to minimize exposure to air, and thelike) are known in the art and may be included in the kit. Kitsdescribed herein can be provided, marketed and/or promoted to healthproviders, including physicians, nurses, pharmacists, formularyofficials, and the like. Kits may also, in some embodiments, be marketeddirectly to the consumer.

Combination Therapies:

The present invention also provides methods for further combinationtherapies in which, in addition to a HIF-2α inhibitor, one or moresecond agents known to modulate other pathways, or other components ofthe same pathway, or even overlapping sets of target proteins is used,or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrateor derivative thereof. In one aspect, such therapy includes but is notlimited to the combination of the composition comprising a HIF-2αinhibitor as described herein with one or more of other HIF-2αinhibitors as described herein, chemotherapeutic agents, therapeuticantibodies, and radiation treatment, to provide, where desired, asynergistic or additive therapeutic effect.

Second agents useful in the methods of the invention include any agentcapable of modulating a target molecule, either directly or indirectly.Non-limiting examples of target molecules modulated by second agentsinclude enzymes, enzyme substrates, products of transitions, antibodies,antigens, membrane proteins, nuclear proteins, cytosolic proteins,mitochondrial proteins, lysosomal proteins, scaffold proteins, lipidrafts, phosphoproteins, glycoproteins, membrane receptors,G-protein-coupled receptors, nuclear receptors, protein tyrosinekinases, protein serine/threonine kinases, phosphatases, proteases,hydrolases, lipases, phospholipases, ligases, reductases, oxidases,synthases, transcription factors, ion channels, RNA, DNA, RNAse, DNAse,phospholipids, sphingolipids, nuclear receptors, ion channel proteins,nucleotide-binding proteins, calcium-binding proteins, chaperones, DNAbinding proteins, RNA binding proteins, scaffold proteins, tumorsuppressors, cell cycle proteins, and histones.

Second agents may target one or more signaling molecules including butnot limited to the following: 4EPB-1, 5-lipoxygenase, A1, Ab1,Acetyl-CoAa Carboxylase, actin, adaptor/scaffold proteins, adenylylcyclase receptors, adhesion molecules, AFT, Akt1, Akt2, Akt3, ALK,AMPKs, APC/C, ARaf, Arf-GAPs, Arfs, ASK, ASK1, asparagine hydroxylaseFIH transferases, ATF2, ATF-2, ATM, ATP citrate lyase, ATR, Auroras, Bcell adaptor for PI3-kinase (BCAP), Bad, Bak, Bax, Bcl-2, Bcl-B, Bcl-w,Bcl-XL, Bid, Bik, Bim, BLNK, Bmf, BMP receptors, Bok, BRAF, Btk, Bub,cadherins, CaMKs, Casein kinases, Caspase 2, Caspase 3, Caspase 6,Caspase 7, Caspase 8, Caspase 9, caspases, catenins, cathepsins,caveolins, Cb1, CBP/P300 family, CD45, CDC25 phosphatases, Cdc42, Cdk 1,Cdk 2, Cdk 4, Cdk 6, Cdk 7, Cdks, CENPs, Chk1, Chk2, CLKs, Cot, cRaf,CREB, Crk, CrkL, Csk, Cyclin A, Cyclin B, Cyclin D, Cyclin E, Db1,deacetylases, DLK, DNA methyl transferases, DNA-PK, Dok, DualSpecificity phosphatases (DUSPs), E2Fs, eg5/KSP, Egr-1, eIF4E-bindingprotein, Elk, elongation factors, endosomal sorting complex required fortransport (ESCRT) proteins, Eph receptors, Erks, esterases, Ets, Eyesabsent (EYA) tyrosine phosphatases, FAK, Fas associated death domain(FADD), FGF receptors, Fgr, focal adhesion kinase, fodrin, Fos, FOXO,Fyn, GAD, Grb2, Grb2 associated binder (GAB), GSK3α, GSK3β, H-Ras,H3K27, Hdm, HER receptors, HIFs, histone acetylases, histonedeacetylases, Histone H3K4 demethylases, HMGA, Hrk, Hsp27, Hsp70,Hsp90s, hydrolases, hydroxylases, IAPs, IGF receptors, IKKs, IL-2, IL-4,IL-6, IL-8, ILK, Immunoglobulin-like adhesion molecules, initiationfactors, inositol phosphatases, Insulin receptor, integrins, interferonα, interferon β, IRAKs, Jak1, Jak2, Jak3, JHDM2A, Jnks, K-Ras, Kitreceptor, KSR, LAR phosphatase, LAT, Lck, Lim kinase, LKB-1, Lowmolecular weight tyrosine phosphatase, Lyn, MAP kinase phosphatases(MKPs), MAPKAPKs, MARKs, Mcl-1, Mek 1, Mek 2, MEKKs, MELK, Met receptor,metabolic enzymes, metalloproteinases, MKK3/6, MKK4/7, MLKs, MNKs,molecular chaperones, Mos, mTOR, multi-drug resistance proteins,muscarinic receptors, Myc, MyD88, myosin, myosin binding proteins,myotubularins, MYST family, Myt 1, N-Ras, Nck, NFAT, NIK, nitric oxidesynthase, Non receptor tyrosine phosphatases (NPRTPs), Noxa, nucleosidetransporters, p130CAS, p14Arf, p16, p21CIP, p27KIP, p38s, p53, p70S6Kinase, p90Rsks, PAKs, paxillin, PDGF receptors, PDK1, P-Glycoprotein,phopsholipases, phosphoinositide kinases, PI3-Kinase class 1, Pim1,Pim2, Pim3, Pin1 prolyl isomerase, PKAs, PKCs, PKR, potassium channels,PP1, PP2A, PP2B, PP2C, PP5, PRK, Prks, prolyl-hydroxylases PHD-1,prostaglandin synthases, pS6, PTEN, Puma, RABs, Rac, Ran, Ras-GAP, Rb,Receptor protein tyrosine phosphatases (RPTPs), Rel-A (p65-NFKB), Ret,RHEB, Rho, Rho-GAPs, RIP, RNA polymerase, ROCK 1, ROCK 2, SAPK/JNK1,2,3,SCF ubiquitination ligase complex, selectins, separase, serinephosphatases, SGK1, SGK2, SGK3, Shc, SHIPs, SHPs, sirtuins, SLAP,Slingshot phosphatases (SSH), Smac, SMADs, small molecular weightGTPases, sodium channels, Sos, Sp1, sphingomyelinases, sphingosinekinases, Src, SRFs, STAT1, STAT3, STAT4, STAT5, STAT6, suppressors ofcytokine signaling (SOCs), Syk, T-bet, T-Cell leukemia family, TCFs,TGFβ receptors, Tiam, TIE1, TIE2, topoisomerases, Tp1, TRADD, TRAF2, Trkreceptors, TSC1,2, tubulin, Tyk2, ubiquitin proteases, urokinase-typeplasminogen activator (uPA) and uPA receptor (uPAR) system, UTX, Vav,VEGF receptors, vesicular protein sorting (Vsps), VHL, Wee1, WT-1, WT-1,XIAP, Yes, ZAP70, β-adrenergic receptors and β-catenin.

In one aspect, this invention also relates to methods and pharmaceuticalcompositions for inhibiting abnormal cell growth in a mammal whichcomprises an amount of a HIF-2α inhibitor, or a pharmaceuticallyacceptable salt, ester, prodrug, solvate, hydrate or derivative thereof,in combination with an amount of an anti-cancer agent (e.g., achemotherapeutic agent). Many chemotherapeutics are presently known inthe art and can be used in combination with the compounds of theinvention.

In some embodiments, the chemotherapeutic is selected from the groupconsisting of mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, angiogenesis inhibitors, immunotherapeuticagents, proapoptotic agents, and anti-androgens. Non-limiting examplesare chemotherapeutic agents, cytotoxic agents, and non-peptide smallmolecules such as Tykerb/Tyverb (lapatinib), Gleevec (ImatinibMesylate), Velcade (bortezomib), Casodex (bicalutamide), Iressa(gefitinib), and Adriamycin as well as a host of chemotherapeuticagents. Non-limiting examples of chemotherapeutic agents include2,2′,2″-trichlorotriethylamine; 2-ethylhydrazide; aceglatone;aldophosphamide glycoside; alkyl sulfonates such as busulfan,improsulfan and piposulfan; alkylating agents such as thiotepa andcyclosphosphamide (CYTOXAN™); aminolevulinic acid; amsacrine;anti-adrenals such as aminoglutethimide, mitotane, trilostane;antibiotics such as anthracyclins, actinomycins and bleomycins includingaclacinomysins, actinomycin, anthramycin, azaserine, bleomycins,cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin,Casodex™, chromomycins, dactinomycin, daunorubicin, detorubicin,6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin,olivomycins, peplomycin, potfiromycin, puromycin, quelamycin,rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex,zinostatin, zorubicin; anti-metabolites such as methotrexate and5-fluorouracil (5-FU); arabinoside (“Ara-C”); aziridines such asbenzodopa, carboquone, meturedopa, and uredopa; bestrabucil; bisantrene;capecitabine; cyclophosphamide; dacarbazine; defofamine; demecolcine;diaziquone; edatraxate; elfomithine; elliptinium acetate; esperamicins;ethylenimines and methylamelamines including altretamine,triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; etoglucid; folicacid analogues such as denopterin, methotrexate, pteropterin,trimetrexate; folic acid replenisher such as frolinic acid; gacytosine;gallium nitrate; gemcitabine; hydroxyurea; lentinan; lonidamine;mannomustine; mitobronitol; mitoguazone; mitolactol; mitoxantrone;mopidamol; nitracrine; nitrogen mustards such as chlorambucil,chlornaphazine, cholophosphamide, estramustine, ifosfamide,mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard;nitrosoureas; nitrosoureas such as carmustine, chlorozotocin,fotemustine, lomustine, nimustine, ranimustine; oxazaphosphorines;pentostatin; phenamet; pipobroman; pirarubicin; podophyllinic acid;procarbazine; PSK®; purine analogs such as fludarabine,6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such asancitabine, azacitidine, 6-azauridine, carmofur, cytarabine,dideoxyuridine, doxifluridine, enocitabine, floxuridine, androgens suchas calusterone, dromostanolone propionate, epitiostanol, mepitiostane,testolactone; razoxane; retinoic acid; sizofiran; spirogermanium;taxanes, e.g., paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology,Princeton, N.J.) and docetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony,France); tenuazonic acid; thiotepa; triazenes; triaziquone; urethan;vindesine; and pharmaceutically acceptable salts, acids or derivativesof any of the above. Also included as suitable chemotherapeutic cellconditioners are anti-hormonal agents that act to regulate or inhibithormone action on tumors such as anti-estrogens including for exampletamoxifen (Nolvadex™), raloxifene, aromatase inhibiting 4(5)-imidazoles,4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, andtoremifene (Fareston); and anti-androgens such as flutamide, nilutamide,bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine;6-thioguanine; mercaptopurine; methotrexate; platinum or platinumanalogs and complexes such as cisplatin and carboplatin;anti-microtubule such as diterpenoids, including paclitaxel anddocetaxel, or Vinca alkaloids including vinblastine, vincristine,vinflunine, vindesine, and vinorelbine; etoposide (VP-16); ifosfamide;mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine;novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate;topoisomerase I and II inhibitors including camptothecins (e.g.,camptothecin-11), topotecan, irinotecan, and epipodophyllotoxins;topoisomerase inhibitor RFS 2000; epothilone A or B;difluoromethylornithine (DMFO); histone deacetylase inhibitors;compounds which induce cell differentiation processes; gonadorelinagonists; methionine aminopeptidase inhibitors; compoundstargeting/decreasing a protein or lipid kinase activity; compounds whichtarget, decrease or inhibit the activity of a protein or lipidphosphatase; anti-androgens; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; compounds used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors; temozolomide (TEMODAL®); Hsp90 inhibitors such as 17-AAG(17-allylaminogeldanamycin, NSC330507), 17-DMAG(17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545),IPI-504, CNF 1010, CNF2024, CNF 1010 from Conforma Therapeutics;temozolomide (TEMODAL®); kinesin spindle protein inhibitors, such asSB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazinefrom CombinatoRx; MEK inhibitors such as ARRY142886 from ArrayPioPharma, AZD6244 from AstraZeneca, PD181461 or PD0325901 from Pfizer,leucovorin, EDG binders, antileukemia compounds, ribonucleotidereductase inhibitors, S-adenosylmethionine decarboxylase inhibitors,antiproliferative antibodies or other chemotherapeutic compounds. Wheredesired, the compounds or pharmaceutical composition of the presentinvention can be used in combination with commonly prescribedanti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®,Taxol®, Arimidex®, Taxotere®, and Velcade®.

This invention further relates to a method for using the compounds orpharmaceutical composition in combination with other tumor treatmentapproaches, including surgery, ionizing radiation, photodynamic therapy,or implants, e.g., with corticosteroids, hormones, or used asradiosensitizers.

One such approach may be, for example, radiation therapy in inhibitingabnormal cell growth or treating the proliferative disorder in themammal. Techniques for administering radiation therapy are known in theart, and these techniques can be used in the combination therapydescribed herein. The administration of the compound of the invention inthis combination therapy can be determined as described herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g., At-211,I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner of the present invention include both solids andliquids. By way of non-limiting example, the radiation source can be aradionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source,I-125 as a solid source, or other radionuclides that emit photons, betaparticles, gamma radiation, or other therapeutic rays. The radioactivematerial can also be a fluid made from any solution of radionuclide(s),e.g., a solution of I-125 or I-131, or a radioactive fluid can beproduced using a slurry of a suitable fluid containing small particlesof solid radionuclides, such as Au-198, Y-90. Moreover, theradionuclide(s) can be embodied in a gel or radioactive micro spheres.

Without being limited by any theory, the compounds of the presentinvention can render abnormal cells more sensitive to treatment withradiation for purposes of killing and/or inhibiting the growth of suchcells. Accordingly, this invention further relates to a method forsensitizing abnormal cells in a mammal to treatment with radiation,which comprises administering to the mammal an amount of a HIF-2αinhibitor or a pharmaceutically acceptable salt, ester, prodrug,solvate, hydrate or derivative thereof, which is effective insensitizing abnormal cells to treatment with radiation. The amount ofthe compound in this method can be determined according to the means forascertaining effective amounts of such compounds described herein.

Further therapeutic agents that can be combined with a subject compoundmay be found in Goodman and Gilman's “The Pharmacological Basis ofTherapeutics” Tenth Edition edited by Hardman, Limbird and Gilman or thePhysician's Desk Reference, both of which are incorporated herein byreference in their entirety.

In some embodiments, the compositions and methods further compriseadministering, separately or simultaneously one or more additionalagents (e.g. 1, 2, 3, 4, 5, or more). Additional agents can includethose useful in wound healing. Non-limiting examples of additionalagents include antibiotics (e.g. Aminoglycosides, Cephalosporins,Chloramphenicol, Clindamycin, Erythromycins, Fluoroquinolones,Macrolides, Azolides, Metronidazole, Penicillin's, Tetracycline's,Trimethoprim-sulfamethoxazole, Vancomycin), steroids (e.g. Andranes(e.g. Testosterone), Cholestanes (e.g. Cholesterol), Cholic acids (e.g.Cholic acid), Corticosteroids (e.g. Dexamethasone), Estraenes (e.g.Estradiol), Pregnanes (e.g. Progesterone), narcotic and non-narcoticanalgesics (e.g. Morphine, Codeine, Heroin, Hydromorphone, Levorphanol,Meperidine, Methadone, Oxydone, Propoxyphene, Fentanyl, Methadone,Naloxone, Buprenorphine, Butorphanol, Nalbuphine, Pentazocine),chemotherapy (e.g. anti-cancer drugs such as but not limited toAltretamine, Asparaginase, Bleomycin, Busulfan, Carboplatin, Carmustine,Chlorambucil, Cisplatin, Cladribine, Cyclophosphamide, Cytarabine,Dacarbazine, Diethylstilbesterol, Ethinyl estradiol, Etoposide,Floxuridine, Fludarabine, Fluorouracil, Flutamide, Goserelin,Hydroxyurea, Idarubicin, Ifosfamide, Leuprolide, Levamisole, Lomustine,Mechlorethamine, Medroxyprogesterone, Megestrol, Melphalan,Mercaptopurine, Methotrexate, Mitomycin, Mitotane, Mitoxantrone,Paclitaxel, pentastatin, Pipobroman, Plicamycin, Prednisone,Procarbazine, Streptozocin, Tamoxifen, Teniposide, Vinblastine,Vincristine), anti-inflammatory agents (e.g. Alclofenac; AlclometasoneDipropionate; Algestone Acetonide; alpha Amylase; Amcinafal; Amcinafide;Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac;Anitrazafen; Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen;Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide;Carprofen; Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate;Clobetasone Butyrate; Clopirac; Cloticasone Propionate; CormethasoneAcetate; Cortodoxone; Decanoate; Deflazacort; Delatestryl;Depo-Testosterone; Desonide; Desoximetasone; Dexamethasone Dipropionate;Diclofenac Potassium; Diclofenac Sodium; Diflorasone Diacetate;Diflumidone Sodium; Diflunisal; Difluprednate; Diftalone; DimethylSulfoxide; Drocinonide; Endrysone; Enlimomab; Enolicam Sodium;Epirizole; Etodolac; Etofenamate; Felbinac; Fenamole; Fenbufen;Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone;Fluazacort; Flufenamic Acid; Flumizole; Flunisolide Acetate; Flunixin;Flunixin Meglumine; Fluocortin Butyl; Fluorometholone Acetate;Fluquazone; Flurbiprofen; Fluretofen; Fluticasone Propionate;Furaprofen; Furobufen; Halcinonide; Halobetasol Propionate; HalopredoneAcetate; Ibufenac; Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol;Ilonidap; Indomethacin; Indomethacin Sodium; Indoprofen; Indoxole;Intrazole; Isoflupredone Acetate; Isoxepac; Isoxicam; Ketoprofen;Lofemizole Hydrochloride; Lomoxicam; Loteprednol Etabonate;Meclofenamate Sodium; Meclofenamic Acid; Meclorisone Dibutyrate;Mefenamic Acid; Mesalamine; Meseclazone; Mesterolone;Methandrostenolone; Methenolone; Methenolone Acetate; MethylprednisoloneSuleptanate; Morniflumate; Nabumetone; Nandrolone; Naproxen; NaproxenSodium; Naproxol; Nimazone; Olsalazine Sodium; Orgotein; Orpanoxin;Oxandrolane; Oxaprozin; Oxyphenbutazone; Oxymetholone; ParanylineHydrochloride; Pentosan Polysulfate Sodium; Phenbutazone SodiumGlycerate; Pirfenidone; Piroxicam; Piroxicam Cinnamate; PiroxicamOlamine; Pirprofen; Prednazate; Prifelone; Prodolic Acid; Proquazone;Proxazole; Proxazole Citrate; Rimexolone; Romazarit; Salcolex;Salnacedin; Salsalate; Sanguinarium Chloride; Seclazone; Sermetacin;Stanozolol; Sudoxicam; Sulindac; Suprofen; Talmetacin; Talniflumate;Talosalate; Tebufelone; Tenidap; Tenidap Sodium; Tenoxicam; Tesicam;Tesimide; Testosterone; Testosterone Blends; Tetrydamine; Tiopinac;Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide;Triflumidate; Zidometacin; Zomepirac Sodium), or anti-histaminic agents(e.g. Ethanolamines (like diphenhydrmine carbinoxamine), Ethylenediamine(like tripelennamine pyrilamine), Alkylamine (like chlorpheniramine,dexchlorpheniramine, brompheniramine, triprolidine), otheranti-histamines like astemizole, loratadine, fexofenadine,Bropheniramine, Clemastine, Acetaminophen, Pseudoephedrine,Triprolidine).

Examples Example 1 Synthesis of(6R,7S)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol(Compound 1) and(R)-4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol(Compound 2)

Step A: Preparation of4-bromo-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one

A suspension of 4-bromo-5,6-dihydrocyclopenta[c]pyridin-7-one (1.0 g,4.72 mmol) and bis(((trifluoromethyl)sulfinyl)oxy)zinc (4.69 g, 14.15mmol) in a mixture of dichloromethane (30 mL) and water (15 mL) at 0° C.was treated with tert-butyl hydroperoxide (˜70% in water, 2.58 mL, 18.86mmol, added via pipette using a plastic tip) and stirred overnight.Additional portions of bis(((trifluoromethyl)sulfinyl)oxy)zinc (2.35 g,7.07 mmol) and tert-butyl hydroperoxide (2.58 mL, 18.86 mmol) were addedsequentially to drive the reaction to completion. After stirring for anadditional day, the reaction vessel was placed into a water bath andcarefully quenched by the addition of saturated NaHCO₃. Onceeffervescence ceased, the reaction mixture filtered through a pad ofcelite to remove. The pad of celite was rinsed with additionaldichloromethane. The filtrate was separated and the aqueous portionextracted further with 2×20 mL CH₂Cl₂. The combined organics were rinsedwith 10 mL of brine, dried with MgSO₄, filtered, and concentrated todryness. Purification was achieved by chromatography on silica using30-90% CH₂Cl₂/hexane to afford4-bromo-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one asan off-white solid (390 mg, 30%). The desired regioisomer elutes first.LCMS ESI (+) (M+H) m/z 280/282.

Step B: Preparation of4-bromo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]and4-bromo-1-(trifluoromethyl)-7-(2-((trimethylsilyl)oxy)ethoxy)-5H-cyclopenta[c]pyridine

Trimethylsilyl trifluoromethanesulfonate (75.9 μL, 0.42 mmol) was addedto a solution of4-bromo-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-7-one (389mg, 1.39 mmol) and trimethyl(2-trimethylsilyloxyethoxy)silane (1.37 mL,5.56 mmol) in dichloromethane (13.6 mL) cooled in an ice bath. Themixture was allowed to slowly warm to ambient temperature. After 5 h, anadditional 1.3 mL of trimethyl(2-trimethylsilyloxyethoxy)silane and 76μL of trimethylsilyl trifluoromethanesulfonate were added. After another16 h, the reaction mixture was treated with triethylamine (770 μL, 5.56mmol), stirred for 10 min, and then concentrated. The residue wastreated with 20 mL EtOAc and 20 mL of water and the layers separated.The aqueous portion was extracted further with 2×20 mL of EtOAc. Thecombined organic extracts were washed with brine, dried over MgSO₄,filtered, and evaporated. Purification was achieved by chromatography onsilica using 5-20% EtOAc/hexane to afford4-bromo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]as a shite solid (262 mg, 58%) and4-bromo-1-(trifluoromethyl)-7-(2-((trimethylsilyl)oxy)ethoxy)-5H-cyclopenta[c]pyridineas a white solid (170 mg, 31%). Data for4-bromo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]:LCMS ESI (+) (M+H) m/z 324/326. Data for4-bromo-1-(trifluoromethyl)-7-(2-((trimethylsilyl)oxy)ethoxy)-5H-cyclopenta[c]pyridine:¹H NMR (400 MHz, CDCl₃): δ 8.56 (s, 1H), 5.59 (t, 1H), 4.10 (t, 2H),3.96 (t, 2H), 3.36 (d, 2H), 0.15 (s, 9H).

Step C: Preparation of4-bromo-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]

A solution of2-[[4-bromo-1-(trifluoromethyl)-5H-cyclopenta[c]pyridin-7-yl]oxy]ethoxy-trimethyl-silane(146.6 mg, 0.37 mmol) and sodium sulfate (262.7 mg, 1.85 mmol) inacetonitrile (3.7 mL) was stirred for 10 min and then treated withSelectfluor® (145.2 mg, 0.41 mmol) and stirred at 25° C. for 1 h.Volatiles were removed by concentration under reduced pressure. Thereaction mixture was poured into 30 mL of water and extracted with 3×15mL EtOAc. The combined organics were rinsed with 10 mL of brine, driedwith MgSO₄, filtered, and concentrated to dryness. Purification wasachieved by chromatography on silica using 5-20% EtOAc/hexane to afford4-bromo-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]as a white solid (96.2 mg, 76%). LCMS ESI (+) (M+H) m/z 342/344.

Step D: Preparation of6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-oland1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-ol

A solution of4′-bromo-6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine](96.2 mg, 0.2800 mmol) and2-(di-t-butylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl(3.4 mg, 0.007 mmol) in 1,4-dioxane (5.0 mL) was sparged with nitrogenfor 3 mins. The reaction mixture was then treated sequentially withpotassium hydroxide (47.3 mg, 0.84 mmol), water (101 μL, 5.62 mmol) and[2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;di-t-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane(6.0 mg, 0.007 mmol) under continuous nitrogen stream. The vessel wassealed and heated to 80 C for 1 h and 30 min. The reaction mixture wasquenched by the addition of acetic acid (64.3 μL, 1.13 mmol). Thereaction mixture was poured into 75 mL of water and extracted with 4×20mL EtOAc. The combined organics were dried with MgSO₄, filtered, andconcentrated to dryness. The product was used without furtherpurification (87 mg). During the reaction, some of thehydrodefluorinated product formed as an impurity. Data for6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-ol:LCMS ESI (+) (M+H) m/z 280. Data for1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-ol:LCMS ESI (+) (M+H) m/z 262.

Step E: Preparation of4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]and4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]

A solution of impure6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-ol(44.0 mg, 0.16 mmol), polymer supported triphenylphosphine (˜2.06mmol/g, 306.2 mg, 0.63 mmol), and 3,3-difluoro-cyclobutanol (68.1 mg,0.63 mmol) in tetrahydrofuran (3.2 mL) was treated with diisopropylazodicarboxylate (120 μL, 0.61 mmol) and stirred at 60° C. for 2 h. Thereaction mixture was filtered and the filter cake rinsed with 20 mLEtOAc. The filtrate was concentrated and purified by chromatography onsilica using 10-30% EtOAc/hexane to afford a clear solid (39.0 mg, 67%)that was a 2:1 mixture of the fluorinated and hydrodefluorinatedproducts. LCMS ESI (+) (M+H) m/z 370. Data for4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]:LCMS ESI (+) (M+H) m/z 370. Data for4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]:LCMS ESI (+) (M+H) m/z 352.

Step F: Preparation of4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-oneand4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one

A solution of impure4′-(3,3-difluorocyclobutoxy)-6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine](39.0 mg, 0.106 mmol) in dichloromethane (2.0 mL) at 0 C was treatedwith perchloric acid (70% in water, 200 μL) and stirred at 0 C for 3 h.The reaction mixture was quenched by the addition of 5 mL of saturatedaqueous NaHCO₃. The resulting mixture was extracted with 3×15 mL CH₂Cl₂.The combined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. The product was used withoutfurther purification as a 2:1 mixture of fluorinated andhydrodefluorinated ketones. LCMS ESI (+) (M+H) m/z 326. Data for4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one:LCMS ESI (+) (M+H) m/z 326. Data for4-3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one:LCMS ESI (+) (M+H) m/z 308.

Step G: Preparation of(6R,7S)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol(Compound 1) and(R)-4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol(Compound 2)

A solution of impure4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-7-one(33.8 mg, 0.10 mmol) in dichloromethane (4.0 mL) was cooled to 0° C. andsparged with nitrogen for 5 min. During this time formic acid (11.8 μL,0.31 mmol) and triethylamine (28.8 μL, 0.21 mmol) were sequentiallyadded. Once sparging was complete, RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.3mg, 0.002 mmol) was added under a continuous stream of nitrogen. Thereaction vessel was sealed and placed into the refrigerator to reactovernight. Volatiles were removed by concentration under reducedpressure. The residue was purified by chromatography on silica using4-18% EtOAc/CH₂Cl₂ to afford(6R,7S)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol(Compound 1) as a clear solid (5.4 mg, 16%) and(R)-4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol(Compound 2) as a clear solid (7.4 mg, 23%). Data for(6R,7S)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol(Compound 1): Retention time HPLC (14 min)=3.59 min; LCMS ESI (+) (M+H)m/z 328; ¹H NMR (400 MHz, CDCl₃): δ 8.04 (s, 1H), 5.46-5.26 (m, 2H),4.89-4.79 (m, 1H), 3.36-3.08 (m, 4H), 2.91-2.74 (m, 2H), 2.60 (dd, 1H).Data for(R)-4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol(Compound 2): Retention time HPLC (14 min)=3.95 min; LCMS ESI (+) (M+H)m/z 310; ¹H NMR (400 MHz, CDCl₃): δ 7.98 (s, 1H), 5.59-5.54 (m, 1H),4.88-4.79 (m, 1H), 3.24-3.07 (m, 3H), 2.89 (dd, 1H), 2.89-2.74 (m, 2H),2.44-2.34 (m, 1H), 2.28-2.21 (m, 1H), 2.12-2.09 (m, 1H).

Example 2: Synthesis of3-fluoro-5-(((6R,7S)-6-fluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile(Compound 3)

Step A: Preparation of1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-ol

A solution of4′-bromo-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine](226.4 mg, 0.70 mmol) and2-(di-t-butylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl(8.5 mg, 0.017 mmol) in 1,4-dioxane (7.0 mL) was sparged with nitrogenfor 3 mins. The reaction mixture was then treated sequentially withpotassium hydroxide (117.6 mg, 2.10 mmol), water (252 μL, 13.97 mmol)and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane(14.9 mg, 0.017 mmol) under continuous nitrogen stream. The vessel wassealed and heated to 80 C for 1 h and 30 min. The reaction mixture wasquenched by the addition of acetic acid (160 μL, 2.79 mmol). Thereaction mixture was poured into 75 mL of water and extracted with 4×20mL EtOAc. The combined organics were dried with MgSO4, filtered, andconcentrated to dryness. The brown solid was used without furtherpurification. LCMS ESI (−) (M−H) m/z 260.

Step B: Preparation of3-fluoro-5-((1-(trifluoromethyl)-5,6-dihydrospiro[cyclonenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile

A suspension of potassium tert-butoxide (28.4 mg, 0.25 mmol) intetrahydrofuran (1.5 mL) at 0 C was treated with1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-ol(60.0 mg, 0.23 mmol) and stirred at 0 C for 15 min. The resultingmixture was treated with(3-cyano-5-fluoro-phenyl)-(4-methoxyphenyl)iodonium;4-methylbenzenesulfonate (144.8 mg, 0.28 mmol) and heated to 40 C. Thereaction mixture was filtered through a plastic filter cup using EtOActo rinse. Volatiles were removed by concentration under reducedpressure. Purification was achieved by chromatography on silica using10-40% EtOAc/hexane to afford a solid (42 mg, 48%). LCMS ESI (+) (M+H)m/z 381.

Step C: Preparation of3-fluoro-5-((7-oxo-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile

A solution of3-fluoro-5-[1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-yl]oxy-benzonitrile(42.0 mg, 0.11 mmol) in dichloromethane (2.0 mL) at 0 C was treated withperchloric acid (70% in water, 240 μL) and stirred at 0 C for 30 min.The reaction mixture was carefully quenched by the addition of 15 mL ofsaturated NaHCO₃ and extracted with 3×15 mL CH₂Cl₂. The combinedorganics were rinsed with 10 mL of brine, dried with MgSO₄, filtered,and concentrated to dryness. The solid residue was used immediately inthe next step without further purification. LCMS ESI (+) (M+H) m/z 337.

Step D: Preparation of3-((7-((tert-butyldimethylsilyl)oxy)-1-(trifluoromethyl)-5H-cyclopenta[c]pyridin-4-yl)oxy)-5-fluorobenzonitrile

A solution of triethylamine (122 μL, 0.88 mmol) and3-fluoro-5-[[7-oxo-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-4-yl]oxy]benzonitrile(37.0 mg, 0.11 mmol) in dichloromethane (2.2 mL) at 0° C. was treatedwith tert-butyldimethylsilyl triflate (152 ul, 0.66 mmol). The ice bathwas removed and the reaction mixture left to stir for 2 h. The reactionmixture was poured into 30 mL of saturated NaHCO₃ and extracted with3×20 mL CH₂Cl₂. The combined organics were rinsed with 10 mL of brine,dried with MgSO₄, filtered, and concentrated to dryness. The product wasused without further purification. LCMS ESI (+) (M+H) m/z 451.

Step E: Preparation of3-fluoro-5-((6-fluoro-7-oxo-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile

A solution of3-[[7-[tert-butyl(dimethyl)silyl]oxy-1-(trifluoromethyl)-5H-cyclopenta[c]pyridin-4-yl]oxy]-5-fluoro-benzonitrile(49.56 mg, 0.1100 mmol) in acetonitrile (2.2 mL) at 25° C. was treatedwith Selectfluor® (42.9 mg, 0.12 mmol) and stirred at 25° C. for 1 h.Volatiles were removed by concentration under reduced pressure Thereaction mixture was poured into 30 mL of water and extracted with 3×10mL EtOAc. The combined organics were rinsed with 10 mL of brine, driedwith MgSO₄, filtered, and concentrated to dryness. Purification wasachieved by chromatography on silica using 10-25% EtOAc/hexane to afforda thin film (37.8 mg, 97%). LCMS ESI (+) (M+H) m/z 355.

Step F: Preparation of3-fluoro-5-(((6R7S)-6-fluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile(Compound 3)

A solution of3-fluoro-5-[[6-fluoro-7-oxo-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-4-yl]oxy]benzonitrile(15.3 mg, 0.043 mmol) in dichloromethane (1.5 mL) was cooled to 0° C.and sparged with nitrogen for 5 min. During this time formic acid (4.9μL, 0.13 mmol) and triethylamine (12.0 μL, 0.086 mmol) were sequentiallyadded. Once the sparging was complete, RuCl(p-cymene)[(R,R)-Ts-DPEN](0.5 mg, 0.00086 mmol) was added under a continuous stream of nitrogen.The reaction vessel was sealed and placed into the refrigerator to reactovernight. Volatiles were removed by concentration under reducedpressure. The residue was purified by chromatography on silica using10-30% EtOAc/hexane to afford3-fluoro-5-(((6R,7S)-6-fluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile(Compound 3) as a clear solid (11.8 mg, 77%). Retention time HPLC (14min)=4.19 min; LCMS ESI (+) (M+H) m/z 357; ¹H NMR (400 MHz, CDCl₃): δ8.33 (s, 1H), 7.22 (ddd, 1H), 7.10-7.08 (m, 1H), 6.99 (dt, 1H),5.54-5.46 (m, 1H), 5.46-5.28 (m, 1H), 3.26 (ddd, 1H), 3.11 (ddd, 1H),2.67 (dd, 1H).

Example 3: Synthesis of3-fluoro-5-(((6R,7S)-6-fluoro-7-hydroxy-1-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile(Compound 4)

Step A: Preparation of 5-bromo-2-(methylthio)nicotinic acid

A solution of 5-bromo-2-fluoro-pyridine-3-carboxylic acid (3.50 g, 15.91mmol) in DMF (62 mL) at 0° C. was treated with potassium carbonate (2.42g, 17.5 mmol) and vigorously stirred at 0° C. for 7 minutes. During thistime, nitrogen was sparged through the solution. Then sodiumthiomethoxide (1.23 g, 16.7 mmol) was added in one portion to thereaction vessel under continuous nitrogen stream. The reaction vesselwas sealed and the ice bath removed. The solution turned from a tancolor to faint yellow. The reaction mixture was left to stir overnight.The reaction mixture was poured onto 10% citric acid solution inducingprecipitation of a white solid. The solid was filtered and rinsedexhaustively with water. Finally, the white solid was dried overnightunder high vacuum in the presence of solid NaOH and used without furtherpurification (3.63 g, 92%). LCMS ESI (+) (M+H) m/z 248/250.

Step B: Preparation of 5-bromo-4-formyl-2-(methylthio)nicotinic acid

A solution of 2,2,6,6-tetramethyl-piperidine (3.26 mL, 19.35 mmol) intetrahydrofuran (40.3 mL) at −50 C was treated with n-butyllithium(˜2.5M in hexanes, 7.09 mL, 17.73 mmol) and stirred for 5 min. Then5-bromo-2-methylsulfanyl-pyridine-3-carboxylic acid (2.00 g, 8.06 mmol)was added via cannula over 30 min as a solution in 60 mL of THF. Theresulting mixture stirred for 30 min at −50 C. The reaction mixture wasquenched by the addition of N,N-dimethylformamide (0.94 mL, 12.09 mmol).15 minutes following addition of the DMF, the reaction mixture wasquenched by the addition of 40 mL of 10% citric acid solution (aqueous)and the reaction warmed to room temperature. After stirring for 30 min,excess THF removed by concentration under reduced pressure. The leftovermixture was poured into 120 mL of 3% citric acid (aqueous) and extractedwith 3×50 mL EtOAc. The combined organics were dried with MgSO₄,filtered, and concentrated to dryness. 2.41 g of an orange solid wasisolated and used without further purification. The material wascontaminated with about 22% citric acid based on proton integration ofthe unpurified NMR spectra. LCMS ESI (+) (M+H) m/z 276/278.

Step C: Preparation of methyl(E)-5-bromo-4-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-(methylthio)nicotinate

A solution of7-bromo-1-hydroxy-4-methylsulfanyl-1H-furo[3,4-c]pyridin-3-one (2.21 g,8.00 mmol), lithium chloride (anhydrous, 339.1 mg, 8.00 mmol) and ethyl2-diethoxyphosphorylacetate (1.60 mL, 8.00 mmol) in acetonitrile (80 mL)at 25 C was treated with 1;8-Diazabicyclo[5.4.0]undec-7-ene (2.87 mL,19.20 mmol) and stirred at 25 C for 2 h. Initially, the solution isheterogenous with the pyridine being insoluble. Upon addition of the DBUthe solution becomes homogeneous and darkens in color. After 1 h, thereaction appears to be mostly complete. In addition a precipitate hasformed. Volatiles were removed by concentration under reduced pressure.The product residue was solubilized with 25 mL of DMF and treated withdimethyl sulfate (1.89 mL, 20.00 mmol). After 2 h, the reaction mixturewas poured into 300 mL of water and extracted with 4×40 mL Et₂O. Thecombined organics were rinsed with 20 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. Purification was achieved bychromatography on silica using 5-20% EtOAc/hexane to afford methyl(E)-5-bromo-4-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-(methylthio)nicotinate asa white solid (1.90 g, 66%). LCMS ESI (+) (M+H) m/z 360/362.

Step D: Preparation of methyl5-bromo-4-(3-ethoxy-3-oxopropyl)-2-(methylthio)nicotinate

A solution of methyl5-bromo-4-[(E)-3-ethoxy-3-oxo-prop-1-enyl]-2-methylsulfanyl-pyridine-3-carboxylate(1.87 g, 5.19 mmol) and cobalt(ii) chloride hexahydrate (123.5 mg, 0.52mmol) in methanol (20.8 mL) at 0° C. was sparged with nitrogen for 3 minand treated with sodium borohydride (98.2 mg, 2.60 mmol) undercontinuous nitrogen stream. The vessel was sealed and the contentsstirred at 0° C. for 10 min. LCMS at this time indicated partialconsumption of the olefin. An additional portion of sodium borohydride(98.2 mg, 2.60 mmol) was added to drive the reaction to completion. Thereaction mixture was quenched by the addition of 30 mL of saturatedaqueous NH₄Cl. Volatiles were removed by concentration under reducedpressure. The reaction mixture was poured into 30 mL of water andextracted with 3×40 mL EtOAc. The combined organics were rinsed with 10mL of brine, dried with MgSO₄, filtered, and concentrated to dryness.Purification was achieved by chromatography on silica using 5-15%EtOAc/hexane to afford the desired product as a solid (1.08 g, 57%).LCMS ESI (+) (M+H) m/z 362/364.

Step E: Preparation of ethyl4-bromo-1-(methylthio)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one

A solution of methyl5-bromo-4-(3-ethoxy-3-oxo-propyl)-2-methylsulfanyl-pyridine-3-carboxylate(1.08 g, 2.98 mmol) in tetrahydrofuran (29.8 mL) at −78° C. was treatedwith lithium bis(trimethylsilyl)amide (˜1.0 M in THF, 7.16 mL, 7.16mmol) by dropwise addition over 30 minutes. Once the addition wascomplete, LCMS indicated a small amount of starting material remained soan additional 1 mL of lithium bis(trimethylsilyl)amide was added and thereaction allowed to stir for a further 15 minutes. The reaction mixturewas quenched by the addition of 30 mL of saturated aqueous NH₄Cl. THFwas removed by concentration under reduced pressure. The reactionmixture diluted with 60 mL of EtOAc and an additional 30 mL of water. Athick precipitate formed that could be eliminated by the addition of 10%citric acid solution. The reaction mixture was extracted with 3×30 mLEtOAc. The combined organics were rinsed with 10 mL of brine, dried withMgSO₄, filtered, and concentrated to dryness. The intermediate productwas transferred into a microwave tube using 9.1 mL of DMSO. Theresulting mixture was diluted with 900 μL of water. The vessel wassealed and heated to 150 C by microwave irradiation for 40 min. Thereaction mixture was diluted with 120 mL of water to induceprecipitation of the product and vigorously stirred for 30 min. Theprecipitate was collected, dried overnight under high vacuum in thepresence of solid NaOH, and used without further purification. Beigesolid (705 mg, 92%). LCMS ESI (+) (M+H) m/z 258/260.

Step F: Preparation of4-bromo-1-(methylsulfonyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one

A solution of4-bromo-1-methylsulfanyl-5,6-dihydrocyclopenta[c]pyridin-7-one (364.5mg, 1.41 mmol) in methanol (11.3 mL) at 0° C. was treated with asolution of Oxone® (1.91 g, 3.11 mmol) in water (11.3 mL). The reactionwas left to stir for 24 h. Volatiles were removed by concentration underreduced pressure. The reaction mixture was poured into 40 mL of waterand extracted with 3×20 mL EtOAc. The combined organics were rinsed with10 mL of brine, dried with MgSO₄, filtered, and concentrated to dryness.The off white solid was used without further purification. LCMS ESI (+)(M+H) m/z 290/292.

Step G: Preparation of4-bromo-1-(methylsulfonyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]

Trimethylsilyl trifluoromethanesulfonate (331 μL, 1.83 mmol) was addedto a solution of4-bromo-1-methylsulfonyl-5,6-dihydrocyclopenta[c]pyridin-7-one (354 mg,1.22 mmol) and trimethyl(2-trimethylsilyloxyethoxy)silane (1.20 mL, 4.88mmol) in dichloromethane (14 mL) cooled in an ice bath. The ice bath wasremoved. After 3 h, an additional portion oftrimethyl(2-trimethylsilyloxyethoxy)silane (1.20 mL, 4.88 mmol) wasadded. The reaction was left to stir overnight. After stirring, for therest of the day, the reaction was quenched by the addition oftriethylamine (1.02 mL, 7.32 mmol). The reaction mixture stirred for 10min. Volatiles were removed and the residue suspended into 30 mL ofsaturated aqueous NaHCO₃ and extracted with 3×20 mL EtOAc. The combinedorganics were rinsed with 10 mL of brine, dried with MgSO4, filtered,and concentrated to dryness. Purification was achieved by chromatographyon silica using 15-50% EtOAc/hexane to afford4-bromo-1-(methylsulfonyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]as a white solid (74.5 mg, 18%). LCMS ESI (+) (M+H) m/z 334/336. Thebulk of the product was isolated as the enol ether (295 mg, 59%).

Step H: Preparation of1-(methylsulfonyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-ol

A solution of4′-bromo-1′-methylsulfonyl-spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine](74.5 mg, 0.22 mmol) and2-(di-t-butylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl(5.4 mg, 0.011 mmol) in 1,4-dioxane (1.5 mL) was sparged with nitrogenfor 3 mins. The reaction mixture was then treated sequentially withpotassium hydroxide (37.5 mg, 0.67 mmol), water (80.3 μL, 4.46 mmol) and[2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane(9.5 mg, 0.011 mmol) under continuous nitrogen stream. The vessel wassealed and heated to 80 C for 1 h and 30 min. The reaction mixture wasquenched by the addition of acetic acid (51.0 μL, 0.89 mmol). Thereaction mixture was poured into 75 mL of water and extracted with 4×20mL EtOAc. The combined organics were dried with MgSO₄, filtered, andconcentrated to dryness. The product was used without furtherpurification (77.9 mg). LCMS ESI (+) (M+H) m/z 272.

Step I: Preparation of3-fluoro-5-((1-(methylsulfonyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile

A suspension of potassium carbonate (30.6 mg, 0.22 mmol) in acetonitrile(1.5 mL) at 25 C was treated with1′-methylsulfonylspiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-ol(40.0 mg, 0.15 mmol) and stirred at 25 C for 10 min. The resultingmixture was treated with(3-cyano-5-fluoro-phenyl)-(4-methoxyphenyl)iodonium;4-methylbenzenesulfonate (116.2 mg, 0.22 mmol) and heated to 50 C for 3h. Volatiles were removed by concentration under reduced pressure. Thereaction mixture was poured into 20 mL of water and extracted with 3×15mL EtOAc. The combined organics were rinsed with 10 mL of brine, driedwith MgSO₄, filtered, and concentrated to dryness. Purification wasachieved by chromatography on silica using 20-50% EtOAc/hexane to afford(3-fluoro-5-((1-(methylsulfonyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrileas a solid (25.1 mg, 44%). LCMS ESI (+) (M+H) m/z 391.

Step J: Preparation of3-fluoro-5-((1-(methylsulfonyl)-7-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile

A solution of4′-(3,3-difluorocyclobutoxy)-6′-fluoro-1′-methylsulfonyl-spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine](25.1 mg, 0.064 mmol) in dichloromethane (3.0 mL) at 0 C was treatedwith perchloric acid (70% in water, 330 μL) and stirred at 0 C for 2 hand then at room temperature for 30 min. The reaction mixture wascarefully quenched with 5 mL of saturated NaHCO₃/10 mL of water andextracted with 3×15 mL CH₂Cl₂. The combined organics were rinsed with 10mL of brine, dried with MgSO₄, filtered, and concentrated to dryness.The product was used without further purification. LCMS ESI (+) (M+H)m/z 347.

Step K: Preparation of3-((7-((tert-butyldimethylsilyl)oxy)-1-(methylsulfonyl)-5H-cyclopenta[c]pyridin-4-yl)oxy)-5-fluorobenzonitrile

A solution of triethylamine (71.4 μL, 0.51 mmol) and3-fluoro-5-[[7-oxo-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-4-yl]oxy]benzonitrile(22.2 mg, 0.064 mmol) in dichloromethane (3.0 mL) at 0° C. was treatedwith tert-butyldimethylsilyl trifluoromethanesulfonate (58.2 μL, 0.38mmol). The ice bath was removed and the reaction mixture stirred for 2h. The reaction mixture was poured into 30 mL of saturated NaHCO₃ andextracted with 3×20 mL CH₂Cl₂. The combined organics were rinsed with 10mL of brine, dried with MgSO₄, filtered, and concentrated to dryness.The product was used without further purification. LCMS ESI (+) (M+H)m/z 461.

Step L: Preparation of3-fluoro-5-((6-fluoro-1-(methylsulfonyl)-7-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile

A solution of3-[[7-[tert-butyl(dimethyl)silyl]oxy-1-(trifluoromethyl)-5H-cyclopenta[c]pyridin-4-yl]oxy]-5-fluoro-benzonitrile(29.5 mg, 0.064 mmol) in acetonitrile (2.6 mL) at 25° C. was treatedwith Selectfluor® (24.9 mg, 0.070 mmol) and stirred at 25° C. for 1 h.Volatiles were removed by concentration under reduced pressure. Thereaction mixture was poured into 30 mL of water and extracted with 3×10mL EtOAc. The combined organics were rinsed with 10 mL of brine, driedwith MgSO₄, filtered, and concentrated to dryness. Purification wasachieved by chromatography on silica using 10-25% EtOAc/hexane to afford3-fluoro-5-((6-fluoro-1-(methylsulfonyl)-7-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrileas a thin film (11.1 mg, 48%). LCMS ESI (+) (M+H) m/z 365.

Step M: Preparation of3-fluoro-5-(((6R,7S)-6-fluoro-7-hydroxy-1-(methylsulfonyl)-6,7-dihydro-5H-cyclonta[c]pyridin-4-yl)oxy)benzonitrile(Compound 4)

A solution of6-fluoro-4-[(5-fluoro-3-pyridyl)oxy]-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-7-one(11.1 mg, 0.031 mmol) in dichloromethane (2.0 mL) was cooled to 0° C.and sparged with nitrogen for 5 min. During this time formic acid (3.4μL, 0.091 mmol) and triethylamine (8.4 μL, 0.061 mmol) were sequentiallyadded. Once the sparging was complete, RuCl(p-cymene)[(R,R)-Ts-DPEN](0.4 mg, 0.0006 mmol) was added under a continuous stream of nitrogen.The reaction vessel was sealed and put into the refrigerator to reactovernight. Volatiles were removed by concentration under reducedpressure. The residue was purified by chromatography on silica using20-60% EtOAc/hexane to afford3-fluoro-5-(((6R,7S)-6-fluoro-7-hydroxy-1-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile(Compound 4) as a white solid (7.0 mg, 63%). Retention time HPLC (14min)=3.16 min; LCMS ESI (+) (M+H) m/z 367; ¹H NMR (400 MHz, CDCl₃): δ8.27 (s, 1H), 7.25 (ddd, 1H), 7.14 (m, 1H), 7.03 (dt, 1H), 5.69 (dt,1H), 5.53-5.36 (m, 1H), 4.24 (d, 1H), 3.34 (s, 3H), 3.31-3.24 (m, 1H),3.09 (ddd, 1H).

Example 4: Synthesis of4-bromo-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine(Compound 5) and4-(difluoromethylsulfonyl)-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine(Compound 6)

Step A: 4-bromo-1-chloro-6,7-dihydro-5H-cyclopenta[c]pyridine

A mixture of 4-bromo-2,5,6,7-tetrahydrocyclopenta[c]pyridin-1-one (420mg, 1.96 mmol) and POCl₃ (2.20 mL, 23.6 mmol) was heated at reflux for40 hours. After cooling, excess POCl₃ was removed under reducedpressure. The residue was taken up in EtOAc, washed with saturatedaqueous NaHCO₃ and brine, dried and concentrated. The residue waspurified by column chromatography on silica gel (2-10% EtOAc/hexanes) togive 4-bromo-1-chloro-6,7-dihydro-5H-cyclopenta[c]pyridine (207 mg,45%). LCMS ESI (+) m/z 232/234/236 (M+H)⁺.

Step B:4-bromo-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine(Compound 5)

A mixture of 4-bromo-1-chloro-6,7-dihydro-5H-cyclopenta[c]pyridine (62mg, 0.27 mmol), 3,5-difluorophenol (38 mg, 0.29 mmol), cesium carbonate(130 mg, 0.400 mmol) and NMP (1.8 mL) was heated at 90° C. overnightunder nitrogen. The reaction mixture was heated to 140° C. and stirredovernight again. After cooling, the reaction mixture was partitionedbetween EtOAc and water. The aqueous layer was extracted with EtOAc. Thecombined organic layers were washed with brine, dried and concentrated.The residue was purified by Biotage C18 reverse phase flashchromatography (20-95% acetonitrile/water) to give4-bromo-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine(Compound 5, 21 mg, 24%) as a pale yellow solid. LCMS ESI (+) m/z326/328 (M+H)⁺.

Step C:S-[1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl]ethanethioate

To a vial containing a solution of4-bromo-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (20mg, 0.060 mmol) in 1,4-dioxane (0.3 mL) were addedacetylsulfanylpotassium (8.8 mg, 0.080 mmol) and(5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (4.3mg, 0.010 mmol). The mixture was sparged with nitrogen. Thentris(dibenzylideneacetone)dipalladium(0) (3.4 mg, 0.004 mmol) was added,and the vial was sealed and heated at 110° C. for 4 hours. Aftercooling, the reaction mixture was filtered through Celite. The filtratewas concentrated. The residue was purified by Biotage C18 reverse phaseflash chromatography (10-80% acetonitrile/water) to giveS-[1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl]ethanethioate (10 mg, 51%). LCMS ESI (+) m/z 322 (M+H)⁺.

Step D:1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-thiol

To a stirred solution ofS-[1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl]ethanethioate(10 mg, 0.030 mmol) in MeOH (0.3 mL) was added 1 N LiOH solution (0.050mL, 0.050 mmol). The reaction mixture was stirred at ambient temperaturefor 30 minutes and then concentrated. To the residue was added water.The pH was added to 2-3 using 0.1 N HCl. The mixture was extracted withEtOAc. The combined organic layers were washed with brine, dried andconcentrated. The crude was used in the next step without furtherpurification. LCMS ESI (+) m/z 280 (M+H)⁺.

Step E:4-(difluoromethylsulfanyl)-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine

To a stirred solution of crude1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-thiol (9mg, 0.03 mmol) in acetonitrile (0.3 mL) was added potassium hydroxide(36 mg, 0.64 mmol) in water (0.3 mL). The reaction mixture was purgedwith nitrogen and then cooled to −78° C. Bromodifluoromethyldiethylphosphonate (17 mg, 0.060 mmol) was added. The resulting mixturewas allowed to warm to ambient temperature and stirred for 3 hours. Thereaction mixture was partitioned between EtOAc and water. The aqueouslayer was extracted with EtOAc. The combined organics were washed withwater and brine, dried over Na₂SO4, filtered, and concentrated todryness. The crude was used in the next step without furtherpurification. LCMS ESI (+) m/z 330 (M+H)⁺.

Step F:4-(difluoromethylsulfonyl)-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine(Compound 6)

Sodium periodate (18 mg, 0.080 mmol) was added all at once to crude4-(difluoromethylsulfanyl)-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine(11 mg, 0.030 mmol) and ruthenium(III) chloride (0.2 mg, 0.001 mmol) inacetonitrile (0.2 mL)/CCl₄ (0.2 mL)/water (0.4 mL). The reaction mixturewas stirred at ambient temperature for 3 hours. Solids were removed byfiltration and rinsed with CH₂Cl₂. The organic layer was separated. Theaqueous layer was extracted with CH₂Cl₂. The combined organics werewashed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The crude product was purified by column chromatography on silicagel (4-12% EtOAc/hexanes) affording Compound 6 (3 mg, 25% overall yieldfor three steps) as a white solid. LCMS ESI (+) m/z 362 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃): δ 7.49 (s, 1H), 6.80-6.71 (m, 3H), 6.19 (t, 1H), 3.36(t, 2H), 3.06 (t, 2H), 2.31-2.23 (m, 2H).

Example 5: Synthesis of racemic3-fluoro-5-((6R,7S)-6-fluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)benzonitrile(Compound 7)

Step A: Preparation of racemic(6R,7S)-4-bromo-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol

A solution of4-bromo-6-fluoro-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-7-one(6.7 mg, 0.022 mmol) in methanol (0.8 mL) at 0° C. was treated withsodium borohydride (0.9 mg, 0.022 mmol) and stirred at 0° C. for 10 min.The reaction mixture was quenched by the addition of 0.2 mL of saturatedNH₄Cl. Volatiles were removed by concentration under reduced pressure.The reaction mixture was poured into 20 mL of water and extracted with3×10 mL EtOAc. The combined organics were rinsed with 10 mL of brine,dried with MgSO₄, filtered, and concentrated to dryness. The product wasused without further purification. LCMS ESI (+) (M+H) m/z 300/302.

Step B: Preparation of racemic3-fluoro-5-((6R,7S)-6-fluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)benzonitrile(Compound 7)

A suspension of racemic(6R,7S)-4-bromo-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol(6.7 mg, 0.022 mmol), 3-cyano-5-fluorophenylboronic acid (5.5 mg, 0.033mmol), cesium fluoride (10.5 mg, 0.069 mmol) andbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(0.8 mg, 0.0011 mmol) in a mixture 1,4-dioxane (0.8 mL) and water (80μL) was sparged with nitrogen for 3 mins. The vessel was sealed andheated to 80° C. for 1 h. LCMS indicates product formation. The reactionmixture was poured into 60 mL of water and extracted with 3×20 mL EtOAc.The combined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. Purification was achieved bychromatography on silica using 10-30% EtOAc/hexane to afford racemic3-fluoro-5-((6R,7S)-6-fluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)benzonitrile(Compound 7) as an orange solid (1.8 mg, 24%). Retention time HPLC (14min)=3.80 min; LCMS ESI (+) (M+H) m/z 341; ¹H NMR (400 MHz, CDCl₃): δ8.65 (s, 1H), 7.53-7.48 (m, 2H), 7.40 (ddd, 1H), 5.56-5.48 (m, 1H), 5.35(ddt, 1H), 3.41 (ddd, 1H), 3.21 (ddd, 1H), 2.65 (dd, 1H).

Example 6: Synthesis of3-(((5R,6S,7S)-5,6-difluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)-5-fluorobenzonitrile(Compound 22)

Step A: Preparation of3-((5-bromo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrile

A suspension of3-fluoro-5-[1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-yl]oxy-benzonitrile(1520 mg, 4 mmol), 2,2′-azobisisobutyronitrile (66 mg, 0.4 mmol),magnesium oxide (483 mg, 12 mmol) and N-bromosuccinimide (925 mg, 5.2mmol) in 1,2-dichloroethane (40 mL) was sparged with nitrogen for 3minutes. The vessel was sealed and heated to 80° C. for 3 h. Additional2,2′-azobisisobutyronitrile (66 mg, 0.4 mmol) and N-bromosuccinimide(925 mg, 5.2 mmol) was added to help drive the reaction to completion.Heating was continued for an additional 1.5 h. The reaction mixture wasleft at room temperature overnight. MgO was removed by filtrationthrough the celite and rinsing of the filter cake with CH₂Cl₂. Thefiltrate was treated with 30 mL of saturated aqueous NaHCO₃, stirred for10 minutes, and extracted with 3×30 mL CH₂Cl₂. The combined organicswere rinsed with 10 mL of brine, dried with MgSO₄, filtered, andconcentrated to dryness. Purification was achieved by chromatography onsilica using 5-25% EtOAc/hexane to afford3-((5-bromo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrileas a yellow foam (931 mg, 51%). LCMS ESI (+) (M+H) m/z 459/461.

Step B: Preparation of3-fluoro-5-((5-hydroxy-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile

A solution of3-[5′-bromo-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-yl]oxy-5-fluoro-benzonitrile(931 mg, 2 mmol) in a mixture of 1,2-dimethoxyethane (15 mL) and water(5 mL) at 25° C. was treated with silver(I) carbonate (1.12 g, 4.1 mmol)and stirred at 85° C. for 8 h. An additional portion of silver(I)carbonate (1.12 g, 4.05 mmol) was added and the reaction mixture left toheat at 85° C. overnight. The reaction mixture was diluted with EtOAcand filtered through celite. The filtrate was washed with water andbrine, dried and concentrated. Purification was achieved bychromatography on silica using 20-55% EtOAc/hexane to afford3-fluoro-5-((5-hydroxy-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrileas a yellow solid (295 mg, 37%). LCMS ESI (+) (M+H) m/z 397.

Step C: Preparation of3-fluoro-5-((5-oxo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile

A solution of3-fluoro-5-[5′-hydroxy-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-yl]oxy-benzonitrile(296 mg, 0.75 mmol) in dichloromethane (15 mL) at 25° C. was treatedwith Dess-Martin periodinane (396 mg, 0.93 mmol). After 1 h, anadditional 20 mg of Dess-Martin periodinane was added. After stirringfor another 30 minutes, the reaction was quenched by the addition of 6mL of saturated Na₂S20₃ solution and 6 mL of saturated NaHCO₃ solution.The resulting biphase was stirred for 10 minutes. The reaction mixturewas poured into 10 mL of water and extracted with 3×20 mL CH₂Cl₂. Thecombined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. The product,3-fluoro-5-((5-oxo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile(264 mg), was used without further purification. LCMS ESI (+) (M+H) m/z395.

Step D: Preparation of3-fluoro-5-((6-fluoro-5-oxo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile

A solution of3-fluoro-5-[5′-oxo-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-6H-cyclopenta[c]pyridine]-4′-yl]oxy-benzonitrile(294 mg, 0.75 mmol) and triethylamine (520 μL, 3.7 mmol) indichloromethane (15 mL) at 0° C. was treated withtert-butyldimethylsilyl trifluoromethane (690 μL, 2.98 mmol) and stirredat 0° C. for 30 minutes. The reaction mixture was left to stir for 5 hduring which it was slowly warmed to room temperature. The reactionmixture was poured into 15 mL of saturated NaHCO₃, stirred for 10minutes, and extracted with 3×15 mL CH₂Cl₂. The combined organics wererinsed with 10 mL of brine, dried with MgSO₄, filtered, and concentratedto dryness. The crude residue was dissolved in 4 mL of acetonitrile andtreated with Selectfluor® (264 mg, 0.75 mmol). The reaction mixture wasstirred for 3 h at room temperature. Volatiles were removed byconcentration under reduced pressure. The mixture was poured into 30 mLof water and extracted with 3×15 mL EtOAc. The combined organics wererinsed with 10 mL of brine, dried with MgSO₄, filtered, and concentratedto dryness. Purification was achieved by chromatography on silica using5-30% EtOAc/hexane to afford3-fluoro-5-((6-fluoro-5-oxo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrileas a white solid (206 mg, 67%). ¹H NMR (400 MHz, CDCl₃): δ 8.51 (s, 1H),7.32-7.28 (m, 1H), 7.21-7.18 (m, 1H), 7.13-7.08 (m, 1H), 5.20 (d, 1H),4.51-4.31 (m, 4H).

Step E: Preparation of3-fluoro-5-(((5R,6R)-6-fluoro-5-hydroxy-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile

A solution of3-fluoro-5-[6′-fluoro-5′-oxo-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-6H-cyclopenta[c]pyridine]-4′-yl]oxy-benzonitrile(206 mg, 0.5 mmol) in dichloromethane (10 mL) was cooled to 0° C. andsparged with nitrogen for 5 minutes. During this time, formic acid (57μL, 1.50 mmol) and triethylamine (104 μL, 0.75 mmol) were sequentiallyadded. Once sparging was complete, RuCl(p-cymene)[(S,S)-Ts-DPEN] (6.4mg, 0.01 mmol) was added under a continuous stream of nitrogen. Thereaction vessel was sealed and put into the refrigerator to reactovernight. Volatiles were removed by concentration under reducedpressure. Purification was achieved by chromatography on silica using20-45% EtOAc/hexane to afford3-fluoro-5-(((5R,6R)-6-fluoro-5-hydroxy-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrileas a clear solid (200 mg, 97%). LCMS ESI (+) (M+H) m/z 415.

Step F: Preparation of(5S,6R)-4-(3-cyano-5-fluorophenoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-5-yl4-nitrobenzoate

A solution of3-fluoro-5-[(5′R,6′R)-6′-fluoro-5′-hydroxy-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-yl]oxy-benzonitrile(200 mg, 0.48 mmol), polymer supported triphenylphosphine (˜2.06 mmol/g,938 mg, 1.93 mmol), and 4-nitrobenzoic acid (323 mg, 1.93 mmol) intetrahydrofuran (9.7 mL) at 25° C. was treated with diisopropylazodicarboxylate (371 μL, 1.88 mmol) and stirred for 2 h. The reactionmixture was filtered and the filter cake rinsed with EtOAc. The filtratewas concentrated and purified by chromatography on silica using 10-35%EtOAc/hexane to afford(5S,6R)-4-(3-cyano-5-fluorophenoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-5-yl4-nitrobenzoate as a white solid (221 mg, 81%). LCMS ESI (+) (M+H) m/z564.

Step G: Preparation of3-fluoro-5-(((5S,6R)-6-fluoro-5-hydroxy-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile

A solution of[(5′S,6′R)-4′-(3-cyano-5-fluoro-phenoxy)-6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-5′-yl]4-nitrobenzoate (238 mg, 0.42 mmol) in tetrahydrofuran (8 mL) at 25° C.was treated with a solution of freshly prepared lithium hydroxidehydrate (19.5 mg, 0.46 mmol) in water (2.4 mL) and stirred at 25° C. for30 minutes. An additional portion of lithium hydroxide hydrate (10 mg,0.24 mmol) in water (1.2 mL) was added and the reaction mixture stirredfor 30 minutes. 2.0 mL of saturated NH₄C was added to the reactionmixture and volatiles were removed under reduced pressure. The reactionmixture was poured into 10 mL of saturated NaHCO₃ and extracted with3×15 mL EtOAc. The combined organics were rinsed with 10 mL of brine,dried with MgSO₄, filtered, and concentrated to dryness. Purificationwas achieved by chromatography on silica using5-10%/EtOAc/dichloromethane to afford3-fluoro-5-(((5S,6R)-6-fluoro-5-hydroxy-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrileas a white solid (137 mg, 78%). LCMS ESI (+) (M+H) m/z 415.

Step H: Preparation of3-(((5R,6S)-5,6-difluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclonenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrile

A solution of3-fluoro-5-[(5′S,6′R)-6′-fluoro-5′-hydroxy-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-yl]oxy-benzonitrile(137 mg, 0.33 mmol) in dichloromethane (6.6 mL) at 25° C. was treatedwith diethylaminosulfur trifluoride (87.4 μL, 0.66 mmol). The reactionmixture was allowed to stir for 30 minutes. The reaction mixture wasquenched by the careful addition of 2 mL of aqueous saturated NaHCO₃.The resulting mixture vigorously stirred for 30 minutes. The reactionmixture was poured into 20 mL of water and extracted with 3×10 mLCH₂Cl₂. The combined organics were rinsed with 10 mL of brine, driedwith MgSO₄, filtered, and concentrated to dryness. Purification wasachieved by chromatography on silica using 10-30% EtOAc/hexane to afford3-(((5R,6S)-5,6-difluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrileas a white solid (92.7 mg, 67%). LCMS ESI (+) (M+H) m/z 417.

Step I: Preparation of3-(((5R,6S,7S)-5,6-difluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)-5-fluorobenzonitrile(Compound 22)

A solution of3-[(5′R,6′S)-5′,6′-difluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-yl]oxy-5-fluoro-benzonitrile(93 mg, 0.22 mmol) in dichloromethane (5 mL) at 0 C was treated with 70%aqueous perchloric acid (1.0 mL) and stirred at 44 C for 3 h. Thereaction mixture was cooled to 0° C., carefully quenched with a mixtureof 10 mL of saturated NaHCO₃/10 mL of water and extracted with 3×15 mLCH₂Cl₂. The combined organics were rinsed with 10 mL of brine, driedwith MgSO₄, filtered, and concentrated to dryness. The intermediateketone product was used immediately without further purification bydissolving in 4 mL of MeOH, cooling to 0° C., and treating with sodiumborohydride (8.4 mg, 0.22 mmol). The reaction stirred for 15 min and wasthen quenched by the addition of 1 mL of saturated NH₄Cl. Volatiles wereremoved by concentration under reduced pressure. The reaction mixturewas poured into 20 mL of water and extracted with 3×10 mL EtOAc. Thecombined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. Purification was achieved bychromatography on silica using 10-45% EtOAc/hexane to afford3-(((5R,6S,7S)-5,6-difluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)-5-fluorobenzonitrileas a white solid (60 mg, 72%). Retention time HPLC (14 min)=4.18minutes; LCMS ESI (+) (M+H) m/z 375; ¹H NMR (400 MHz, CDCl₃): δ 8.42 (s,1H), 7.28 (ddd, 1H), 7.20-7.18 (m, 1H), 7.09 (dt, 1H), 5.92 (dt, 1H),5.53-5.46 (m, 1H), 5.19 (ddt, 1H), 2.66 (ddd, 1H).

Example 7: Synthesis of3-fluoro-5-(((5S,6R)-6-fluoro-5-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl)oxy)benzonitrile(Compound 33)

Step A: Preparation of ethyl (E)-3-(2-fluoro-4-iodopyridin-3-yl)acrylate

A solution of 2-fluoro-4-iodo-3-pyridinecarboxyaldehyde (1.0 g, 4 mmol),lithium chloride (169 mg, 4 mmol) and ethyl 2-diethoxyphosphorylacetate(800 μL, 4 mmol) in acetonitrile (20 mL) at 25° C. was treated with1,8-Diazabicyclo[5.4.0]undec-7-ene (630 μL, 4.2 mmol) and stirred at 25°C. for 2 h. Volatiles were removed by concentration under reducedpressure. The reaction mixture was poured into 30 mL of water andextracted with 3×20 mL EtOAc. The combined organics were rinsed with 10mL of brine, dried with MgSO₄, filtered, and concentrated to dryness.Purification was achieved by chromatography on silica using 100% CH₂Cl₂to afford ethyl (E)-3-(2-fluoro-4-iodopyridin-3-yl)acrylate as whitesolid (1.1 g, 86%). LCMS ESI (+) (M+H) m/z 322.

Step B: Preparation of ethyl(E)-3-(4-cyano-2-fluoropyridin-3-yl)acrylate

A solution of ethyl (E)-3-(2-fluoro-4-iodo-3-pyridyl)prop-2-enoate (900mg, 2.8 mmol) and zinc cyanide (987 mg, 8.4 mmol) inN,N-dimethylacetamide (10 mL) was sparged with nitrogen for 3 minutes.The reaction mixture was then treated sequentially with1,1′-ferrocenediyl-bis(diphenylphosphine) (61 mg, 0.11 mmol) andtris(dibenzylideneacetone)dipalladium(0) (51 mg, 0.056 mmol) undercontinuous nitrogen stream. The vessel was sealed and heated to 110° C.for 30 minutes. The reaction mixture was poured into 100 mL of water andextracted with 3×25 mL TBME. The combined organics were rinsed with 10mL of brine, dried with MgSO₄, filtered, and concentrated to dryness.Purification was achieved by chromatography on silica using 5-25%EtOAc/hexane to afford ethyl(E)-3-(4-cyano-2-fluoropyridin-3-yl)acrylate as a solid (594 mg, 97%).LCMS ESI (+) (M+H) m/z 221.

Step C: Preparation of ethyl 3-(4-cyano-2-fluoropyridin-3-yl)propanoate

A suspension of ethyl (E)-3-(4-cyano-2-fluoro-3-pyridyl)prop-2-enoate(560 mg, 2.54 mmol) and palladium on carbon (10 wt. %, 68 mg, 0.064mmol) in methanol (25 mL) at 25° C. was sparged with nitrogen for 3minutes. Then the solution was sparged with hydrogen for 1 minute andleft under a hydrogen balloon for 3 h. The reaction mixture wascarefully sparged with nitrogen for 3 minutes and then filtered througha pad of celite using MeOH as a rinse. The filtrate was concentrated andpurification was achieved by chromatography on silica using 5-25%EtOAc/hexane to afford ethyl 3-(4-cyano-2-fluoropyridin-3-yl)propanoate(391 mg, 68%). LCMS ESI (+) (M+H) m/z 223.

Step D: Preparation of1-hydroxy-6,7-dihydro-5H-cyclopenta[c]pyridin-5-one

A solution of ethyl 3-(4-cyano-2-fluoro-3-pyridyl)propanoate (384 mg,1.73 mmol) in tetrahydrofuran (10 mL) at −78° C. was treated withlithium bis(trimethylsilyl)amide (1.0 M in THF, 2.25 mL, 2.25 mmol) byslow dropwise addition over 5 minutes. The reaction mixture stirred for20 minutes at this temperature. The reaction was quenched by theaddition of 5 mL of saturated NH₄Cl. Organic volatiles were removed byconcentration under reduced pressure. The reaction mixture was extractedwith 3×20 mL EtOAc. The combined organics were rinsed with 10 mL ofbrine, dried with MgSO₄, filtered, and concentrated to dryness. Theintermediate vinylogous carbamate was suspended in 6.6 mL of dioxane andtreated with 1.3 mL of water and 2.0 mL of concentrated H₂SO₄. Theresulting mixture was heated to 120° C. by microwave irradiation for 45min. Volatiles were removed by concentration under reduced pressure. Thereaction mixture was poured into 30 mL of water and extracted with 5×15mL EtOAc. The combined organics were rinsed with 10 mL of brine, driedwith MgSO₄, filtered, and concentrated to dryness. Purification wasachieved by chromatography on silica using 2-8% MeOH/CH₂Cl₂ to afford1-hydroxy-6,7-dihydro-5H-cyclopenta[c]pyridin-5-one as a beige solid(167 mg, 65%). LCMS ESI (+) (M+H) m/z 150.

Step E: Preparation of5-(2-((trimethylsilyl)oxy)ethoxy)-7H-cyclopenta[c]pyridin-1-ol

Trimethylsilyl trifluoromethanesulfonate (263 μL, 1.46 mmol) was addedto a solution of 1-hydroxy-6,7-dihydrocyclopenta[c]pyridin-5-one (167mg, 1.12 mmol) and trimethyl(2-trimethylsilyloxyethoxy)silane (1.1 mL,4.48 mmol) in dichloromethane (11.2 mL) cooled in an ice bath. The icebath was removed and the reaction stirred at ambient temperatureovernight. The next day, an additional portion of trimethylsilyltrifluoromethanesulfonate (263 μL, 1.46 mmol) was added. After 4 h, thereaction mixture was treated with triethylamine (624 μL, 4.48 mmol),stirred for 10 minutes, and then evaporated. The residue was treatedwith 20 mL of 30% isopropyl alcohol/CHCl₃ and 20 mL water and the layersseparated. The aqueous layer was further extracted with 3×10 mL of 30%isopropyl alcohol/CHCl₃. The combined organic extracts were washed withbrine, dried over MgSO₄, filtered, and evaporated. Purification wasachieved by chromatography on silica using 2-10% MeOH/CH₂Cl₂ to afford aclear solid (105 mg) that was a ˜1:1 mixture of5-(2-((trimethylsilyl)oxy)ethoxy)-7H-cyclopenta[c]pyridin-1-ol and theketalized product,6,7-dihydrospiro[cyclopenta[c]pyridine-5,2′-[1,3]dioxolan]-1-ol. LCMSESI (+) (M+H) m/z 194.

Step F: Preparation of6-fluoro-6,7-dihydrospiro[cyclopenta[c]pyridine-5,2′-[1,3]dioxolan]-1-ol

A mixture of impure5-(2-trimethylsilyloxyethoxy)-7H-cyclopenta[c]pyridin-1-ol (˜105 mg) andsodium sulfate (281 mg, 1.98 mmol) in acetonitrile (7.9 mL) was stirredfor 10 minutes and then treated with Selectfluor® (154 mg, 0.44 mmol)and stirred at 25° C. for 1 h. Volatiles were removed by concentrationunder reduced pressure. The reaction mixture was poured into 30 mL ofwater and extracted with 3×15 mL 30% isopropyl alcohol/CHCl₃. Thecombined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. Purification was achieved bychromatography on silica using 2-10% MeOH/CH₂Cl₂ to afford the desiredproduct with impurities. LCMS ESI (+) (M+H) m/z 212.

Step G: Preparation of3-fluoro-5-((6-fluoro-4-iodo-6,7-dihydrospiro[cyclopenta[c]pyridine-5,2′-[1,3]dioxolan]-1-yl)oxy)benzonitrile

A solution of impurespiro[1,3-dioxolane-2,5′-6,7-dihydrocyclopenta[c]pyridine]-1′-ol (142mg) in acetonitrile (7.3 mL) was treated with N-iodosuccinimide (182 mg,0.81 mmol) and heated to 80° C. over 1 h. Volatiles were removed byconcentration under reduced pressure. The residue was redissolved inacetonitrile (7.3 mL) and treated with potassium carbonate (305 mg, 2.2mmol) and (3-cyano-5-fluoro-phenyl)-(4-methoxyphenyl)iodonium;4-methylbenzenesulfonate (579 mg, 1.1 mmol). The reaction was heated to80° C. for 1 h. The reaction mixture was cooled and recharged withpotassium carbonate (100 mg) and diaryliodonium salt (385 mg). Thereaction mixture was heated to 80° C. for another hour. Volatiles wereremoved by concentration under reduced pressure. The reaction mixturewas poured into 30 mL of water and extracted with 3×20 mL EtOAc. Thecombined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. Purification was achieved bychromatography on silica using 5-25% EtOAc/hexane to afford the desiredproduct with impurities. LCMS ESI (+) (M+H) m/z 338.

Step H: Preparation of3-fluoro-5-((6-fluoro-4-iodo-5-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl)oxy)benzonitrile

A solution of3-fluoro-5-((6-fluoro-4-iodo-6,7-dihydrospiro[cyclopenta[c]pyridine-5,2′-[1,3]dioxolan]-1-yl)oxy)benzonitrile(22 mg, 0.05 mmol) in dichloromethane (1.0 mL) at 0° C. was treated with70% aqueous perchloric acid (200 μL) and stirred at 25° C. for 2 h. Thereaction mixture was cooled to 0° C., carefully quenched with a mixtureof 5 mL of saturated NaHCO₃/10 mL of water and extracted with 3×15 mLCH₂Cl₂. The combined organics were rinsed with 10 mL of brine, driedwith MgSO₄, filtered, and concentrated to dryness. Purification wasachieved by chromatography on silica using 60-100% CH₂Cl₂/hexane toafford the desired product (6.0 mg) as a thin film. LCMS ESI (+) (M+H)m/z 413.

Step I: Preparation of3-fluoro-5-((6-fluoro-5-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl)oxy)benzonitrile

A solution of3-fluoro-5-[(6-fluoro-4-iodo-5-oxo-6,7-dihydrocyclopenta[c]pyridin-1-yl)oxy]benzonitrile(6.0 mg, 0.015 mmol) and copper (2.8 mg, 0.044 mmol) in DMF (0.5 mL) wassparged with nitrogen for 3 minutes. The reaction mixture was then withsulfonium diphenyl(trifluoromethyl)-, 1,1,1-trifluoromethanesulfonate(1:1) (12 mg, 0.03 mmol) under continuous nitrogen stream. The vesselwas sealed and heated to 60° C. for 6 h. The reaction mixture was pouredinto 20 mL of water and extracted with 3×15 mL TBME. The combinedorganics were rinsed with 10 mL of brine, dried with MgSO₄, filtered,and concentrated to dryness. Purification was achieved by chromatographyon silica using 5-25% EtOAc/hexane to afford3-fluoro-5-((6-fluoro-5-oxo-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl)oxy)benzonitrileas a thin film (4.3 mg, 83%). LCMS ESI (+) (M+H) m/z 355.

Step J: Preparation of3-fluoro-5-(((5S,6R)-6-fluoro-5-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl)oxy)benzonitrile(Compound 33)

A solution of3-fluoro-5-[[6-fluoro-5-oxo-4-(trifluoromethyl)-6,7-dihydrocyclopenta[c]pyridin-1-yl]oxy]benzonitrile(4.3 mg, 0.012 mmol) in methanol (1.0 mL) at 0° C. was treated withsodium borohydride (0.5 mg, 0.012 mmol) and stirred at 0 C for 15minutes. The reaction was then quenched by the addition of 1 mL ofsaturated NH₄Cl. Volatiles were removed by concentration under reducedpressure. The reaction mixture was poured into 20 mL of water andextracted with 3×10 mL EtOAc. The combined organics were rinsed with 10mL of brine, dried with MgSO₄, filtered, and concentrated to dryness.Purification was achieved by chromatography on silica using 15-40%EtOAc/hexane to afford3-fluoro-5-(((5S,6R)-6-fluoro-5-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl)oxy)benzonitrileas a thin film (3.6 mg, 83%). Retention time HPLC (14 min)=5.66 minutes;LCMS ESI (+) (M+H) m/z 357; ¹H NMR (400 MHz, CDCl₃): δ 8.36-8.34 (m,1H), 7.35-7.32 (m, 1H), 7.28 (ddd, 1H), 7.23 (dt, 1H), 5.53-5.35 (m,2H), 3.40 (ddd, 1H), 3.22 (ddd, 1H), 2.73-2.68 (m, 1H).

Example 8: Synthesis of5-(((5R,6S,7S)-5,6-difluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)nicotinonitrile(Compound 34)

Step A: Preparation of5-(((5R,6S,7S)-5,6-difluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)nicotinonitrile(Compound 34)

A solution of tetrahydrofuran (2.0 mL) and Water (4.0 mL) was spargedwith nitrogen for 3 minutes. Sparging was ceased and to the solutionwere sequentially added under continuous nitrogen stream(5R,6S,7S)-4-[(5-bromo-3-pyridyl)oxy]-5,6-difluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol(50 mg, 0.12 mmol),[2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (19 mg, 0.024mmol) and zinc cyanide (20 mg, 0.17 mmol). The vessel was sealed andheated to 40° C. for 3 h. An additional portion of[2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (19 mg, 0.024mmol) and zinc cyanide (20 mg, 0.17 mmol) were added and the reactionmixture was heated to 65° C. for 18 h. The reaction mixture was pouredinto 10 mL of saturated NaHCO₃ and extracted with 3×10 mL EtOAc. Thecombined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. Purification was achieved bychromatography on silica using 20-60% EtOAc/hexane to afford5-(((5R,6S,7S)-5,6-difluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)nicotinonitrileas a white solid (34.3 mg, 80%). Retention time HPLC (14 min)=2.55minutes; LCMS ESI (+) (M+H) m/z 358; ¹H NMR (400 MHz, CDCl₃): δ 8.79(dd, 1H), 8.71 (d, 1H), 8.41 (s, 1H), 7.67 (dd, 1H), 5.94 (dt, 1H),5.53-5.46 (m, 1H), 5.21 (ddt, 1H), 2.73 (ddd, 1H).

Example 9: Synthesis of(5R,6S,7S)-4-(3,3-difluorocyclobutoxy)-5,6-difluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol(Compound 37)

Step A: Preparation of4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]

A solution of1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-ol(1.9 g, 7.27 mmol), (3,3-difluorocyclobutyl) 4-methylbenzenesulfonate(2.86 g, 10.9 mmol), potassium iodide (1.81 g, 10.9 mmol) and potassiumcarbonate (2.0 g, 14.6 mmol) in acetonitrile (20 mL) was stirred at 100°C. overnight. The reaction mixture was concentrated to dryness, dilutedwith ethyl acetate (100 mL), washed with water (100 mL) and brine (20mL). The organic phase was collected, dried over anhydrous Na₂SO₄,filtered and the filtrate was concentrated. Purification was achieved bychroamtography on silica using 10-20% EtOAc/petroleum ether to afford4′-(3,3-difluorocyclobutoxy)-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]as a white solid (1.00 g, 2.85 mmol, 39%). LCMS ESI (+) (M+H) m/z 352.(The Mitsunobu reaction can also be used to derivatize the1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-ol.)

Step B: Preparation of5-bromo-4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]

A solution of4′-(3,3-difluorocyclobutoxy)-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine](1.00 g, 2.85 mmol), 2,2′-azobisisobutyronitrile (94 mg, 0.57 mmol),NaHCO₃ (420 mg, 5.0 mmol) and 1-bromopyrrolidine-2,5-dione (1.27 g, 7.12mmol) in 1,2-dichloroethane (20 mL) was sparged with nitrogen for 3minutes. The vessel was sealed and heated to 80° C. for 1 h. Thereaction mixture was poured into 30 mL of saturated aqueous Na₂SO₃ andextracted with 3×30 mL CH₂Cl₂. The combined organics were rinsed with 20mL of brine, dried with MgSO₄, filtered, and concentrated to dryness.Purification was achieved by chromatography on silica using 5-25%EtOAc/hexane to afford5′-bromo-4′-(3,3-difluorocyclobutoxy)-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]as an off-white solid (650 mg, 1.5 mmol, 53%). ¹H NMR (400 MHz, CDCl₃):δ 8.11 (s, 1H), 5.36-5.31 (m, 1H), 4.98-4.88 (m, 1H), 4.36-4.21 (m, 2H),4.16-4.07 (m, 2H), 3.26-3.13 (m, 2H), 2.96-2.71 (m, 4H).

Step C: Preparation of4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-5-ol

A solution of5′-bromo-4′-(3,3-difluorocyclobutoxy)-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine](650 mg, 1.5 mmol) in a mixture of 1,2-dimethoxyethane (15 mL) and water(5 mL) was treated with silver carbonate (417 mg, 1.5 mmol) and stirredat 85° C. overnight. The mixture was diluted with EtOAc and filteredthrough celite. The filtrate was concentrated to remove thedimethoxyethane. The residue was re-suspended in 60 mL of 1:1 EtOAc/H₂Oand extracted with 3×15 mL EtOAc. The combined organics were rinsed with10 mL of brine, dried with MgSO₄, filtered, and concentrated to dryness.Purification was achieved by chromatography on silica using 10-30%EtOAc/hexane to afford4′-(3,3-difluorocyclobutoxy)-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-5′-olas a solid (280 mg, 50%). ¹H NMR (400 MHz, CDCl₃): δ 8.11 (s, 1H),5.39-5.32 (m, 1H), 4.97-4.87 (m, 1H), 4.33-4.20 (m, 2H), 4.17-4.04 (m,2H), 3.27-3.13 (m, 2H), 2.96-2.75 (m, 2H), 2.63 (dd, 1H), 2.53 (d, 1H),2.28 (dd, 1H).

Step D: Preparation of4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)spiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-5(6H)-one

A solution of4′-(3,3-difluorocyclobutoxy)-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-5′-ol(280 mg, 0.76 mmol) in dichloromethane (10 mL) at 25° C. was treatedwith Dess-Martin periodinane (500 mg, 1.18 mmol). After 2 h, thereaction was quenched by the addition of 10 mL of saturated Na₂S20₃solution and 10 mL of saturated NaHCO₃ solution. The resulting biphasestirred for 10 minutes. The reaction mixture was poured into 20 mL ofwater and extracted with 3×20 mL CH₂Cl₂. The combined organics wererinsed with 10 mL of brine, dried with MgSO₄, filtered, and concentratedto dryness to afford4′-(3,3-difluorocyclobutoxy)-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-6H-cyclopenta[c]pyridine]-5′-oneas a solid (270 mg, 97%) that was used without further purification.LCMS ESI (+) (M+H) m/z 366.

Step E: Preparation of4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)spiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-5(6H)-one

A solution of4′-(3,3-difluorocyclobutoxy)-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-6H-cyclopenta[c]pyridine]-5′-one(270 mg, 0.74 mmol) and triethylamine (410 μL, 3 mmol) indichloromethane (10 mL) at 0° C. was treated withtert-butyl-dimethyl-(trifluoromethylsulfonyl)silane (480 μL, 2.2 mmol)and stirred at 0° C. for 30 minutes. The reaction mixture was left tostir overnight at room temperature. The reaction mixture was poured into10 mL of saturated NaHCO₃, stirred for 10 minutes, and extracted with3×15 mL CH₂Cl₂. The combined organics were rinsed with 10 mL of brine,dried with MgSO₄, filtered, and concentrated to dryness. The unpurifiedresidue was dissolved in acetonitrile (10 mL) and treated withSelectfluor® (322 mg, 0.92 mmol). The reaction stirred for 6 h at roomtemperature. Volatiles were removed by concentration under reducedpressure. The reaction mixture was poured into 30 mL of water andextracted with 3×15 mL EtOAc. The combined organics were rinsed with 10mL of brine, dried with MgSO₄, filtered, and concentrated to dryness.Purification was achieved by chromatography on silica using 5-20%EtOAc/hexane to afford4′-(3,3-difluorocyclobutoxy)-6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-6H-cyclopenta[c]pyridine]-5′-oneas a white solid (180 mg, 56%). ¹H NMR (400 MHz, CDCl₃): δ 8.35 (s, 1H),5.13 (d, 1H), 5.01-4.91 (m, 1H), 4.47-4.38 (m, 1H), 4.38-4.26 (m, 3H),3.30-3.14 (m, 2H), 3.04-2.86 (m, 2H).

Step F: Preparation of(5R,6R)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-5-ol

A solution of4′-(3,3-difluorocyclobutoxy)-6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-6H-cyclopenta[c]pyridine]-5′-one(180 mg, 0.47 mmol) in dichloromethane (10 mL) was cooled to 0° C. andsparged with nitrogen for 5 minutes. During this time formic acid (53.1μL, 1.4 mmol) and triethylamine (98.2 μL, 0.70 mmol) were sequentiallyadded. Once sparging was complete, RuCl(p-cymene)[(S,S)-Ts-DPEN] (15 mg,0.023 mmol) was added under a continuous stream of nitrogen. Thereaction vessel was sealed and put into the refrigerator to reactovernight. Volatiles were removed by concentration under reducedpressure. Purification was achieved by chromatography on silica using10-30% EtOAc/hexane to afford(5′R,6′R)-4′-(3,3-difluorocyclobutoxy)-6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-5′-olas a clear solid (152 mg, 84%). LCMS ESI (+) (M+H) m/z 386.

Step G: Preparation of(5S,6R)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-5-yl4-nitrobenzoate

A solution of(5′R,6′R)-4′-(3,3-difluorocyclobutoxy)-6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-5′-ol(124 mg, 0.32 mmol), polymer supported triphenylphosphine (˜2.06 mmol/g,627 mg, 1.29 mmol), and 4-nitrobenzoic acid (216 mg, 1.29 mmol) intetrahydrofuran (3.3 mL) was treated with diisopropyl azodicarboxylate(248 μL, 1.26 mmol) and stirred at 25° C. for 2 h. The reaction mixturewas filtered and the filter cake rinsed with 30 mL EtOAc. The filtratewas concentrated and purified by chromatography on silica using 10-25%EtOAc/hexane to afford(5S,6R)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-5-yl4-nitrobenzoate as a white solid (160 mg, 93%). LCMS ESI (+) (M+H) m/z535.

Step H: Preparation of(5S,6R)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-5-ol

A solution of[(5′S,6′R)-4′-(3,3-difluorocyclobutoxy)-6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-5′-yl]4-nitrobenzoate (194 mg, 0.36 mmol) in tetrahydrofuran (7 mL) at 25° C.was treated with a solution of freshly prepared hydroxylithium hydrate(16.8 mg, 0.4 mmol) in water (2.1 mL) and stirred at 25° C. for 30minutes. An additional portion of hydroxylithium hydrate (8.4 mg, 0.20mmol) in water (1.0 mL) was added and the reaction mixture stirred foranother 30 minutes. Saturated NH₄Cl (0.5 mL) was added and volatileswere removed under reduced pressure. The reaction mixture was pouredinto 10 mL of saturated NaHCO₃ and extracted with 3×15 mL EtOAc. Thecombined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. Purification was achieved bychromatography on silica using 10-35% EtOAc/hexane to afford(5S,6R)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-5-olas a white solid (74 mg, 53%). LCMS ESI (+) (M+H) m/z 386.

Step I: Preparation of(5R,6S)-4-(3,3-difluorocyclobutoxy)-5,6-difluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]

A solution of(5′S,6′R)-4′-(3,3-difluorocyclobutoxy)-6′-fluoro-′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-5′-ol(74 mg, 0.19 mmol) in dichloromethane (3.8 mL) at 25° C. was treatedwith diethylaminosulfur trifluoride (51 μL, 0.38 mmol). The reactionmixture was allowed to stir for 30 minutes. The reaction mixture wasquenched by the careful addition of 1 mL of aqueous saturated NaHCO₃.The resulting mixture stirred for 30 minutes, poured into 20 mL of waterand extracted with 3×15 mL CH₂Cl₂. The combined organics were rinsedwith 10 mL of brine, dried with MgSO₄, filtered, and concentrated todryness. Purification was achieved by chromatography on silica using5-25% EtOAc/hexane to afford(5R,6S)-4-(3,3-difluorocyclobutoxy)-5,6-difluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]as a white solid (72 mg, 97%). LCMS ESI (+) (M+H) m/z 388.

Step J: Preparation of(5R,6S,7S)-4-(3,3-difluorocyclobutoxy)-5,6-difluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol(Compound 37)

A solution of(5′R,6′S)-4′-(3,3-difluorocyclobutoxy)-5′,6′-difluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine](72 mg, 0.19 mmol) in dichloromethane (4.0 mL) at 0° C. was treated with70% aqueous perchloric acid (800 μL). The reaction mixture was heated to44° C. for 5 h. The reaction mixture was cooled to 0° C., carefullyquenched with a mixture of 10 mL of saturated NaHCO₃/10 mL of water andextracted with 3×15 mL CH₂Cl₂. The combined organics were rinsed with 10mL of brine, dried with MgSO₄, filtered, and concentrated to dryness.The product was used immediately without further purification bydissolving in 2 mL of MeOH, cooling to 0° C., and treating with sodiumborohydride (7.0 mg, 0.19 mmol). The reaction stirred for 15 min and wasthen quenched by the addition of 1 mL of saturated NH₄Cl. Volatiles wereremoved by concentration under reduced pressure. The reaction mixturewas poured into 20 mL of water and extracted with 3×15 mL EtOAc. Thecombined organics were rinsed with 10 mL of brine, dried with MgSO₄,filtered, and concentrated to dryness. Purification was achieved bychromatography on silica using 10-40% EtOAc/hexane to afford(5R,6S,7S)-4-(3,3-difluorocyclobutoxy)-5,6-difluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-olas a white solid (53 mg, 83%). Retention time HPLC (14 min)=3.37minutes; LCMS ESI (+) (M+H) m/z 346; ¹H NMR (400 MHz, CDCl₃): δ 8.24 (s,1H), 5.95 (ddd, 1H), 5.47-5.41 (m, 1H), 5.07 (ddt, 1H), 4.97-4.88 (m,1H), 3.30-3.15 (m, 2H), 2.99-2.79 (m, 2H), 2.54-2.49 (m, 1H).

Example 10: Synthesis of3-fluoro-5-((5-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)oxy)benzonitrile(Compound 42)

Step A: Preparation of1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine

A solution of 3,6-dichloro-1,2,4,5-tetrazine (2.5 g, 16.6 mmol) indichloromethane (100 mL) at 0° C. was treated1-(cyclopenten-1-yl)pyrrolidine (2.42 mL, 16.6 mmol) by dropwiseaddition over 15 minutes. After 15 minutes following the addition of theenamine, the reaction was quenched by the addition of 30 mL of 10%aqueous citric acid solution and 30 mL of water. The reaction wasremoved from the ice bath and vigorously stirred for 5 minutes. Thereaction mixture extracted with 3×30 mL CH₂Cl₂. The combined organicswere rinsed with 30 mL of brine, dried with MgSO₄, filtered, andconcentrated to dryness. Purification was achieved by chromatography onsilica using 5-20% EtOAc/hexane to afford1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine as a white solid(1.66 g, 53%). LCMS ESI (+) (M+H) m/z 189/191/193.

Step B: Preparation of5-bromo-1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine

A solution of 1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine (402mg, 2.1 mmol), 2,2′-azobisisobutyronitrile (35 mg, 0.21 mmol) andN-bromosuccinimide (397 mg, 2.23 mmol) in 1,2-dichloroethane (21.3 mL)was sparged with nitrogen for 3 minutes. The vessel was sealed andheated to 80° C. for 2.5 h. Volatiles were removed by concentrationunder reduced pressure. The reaction mixture was poured into 20 mL of0.5 M NaOH and extracted with 3×15 mL CH₂Cl₂. The combined organics wererinsed with 10 mL of brine, dried with MgSO₄, filtered, and concentratedto dryness. The product was used without further purification. LCMS ESI(+) (M+H) m/z 267/269/271.

Step C: Preparation of1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazin-5-ol

A solution of unpurified5-bromo-1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine (563 mg, 2.1mmol) in 1,2-dimethoxyethane (11.4 mL) and water (0.6 mL) at 25° C. wastreated with silver(I) perchlorate hydrate (713 mg, 3.15 mmol) andstirred at 60° C. for 2.5 h. Volatiles were removed by concentrationunder reduced pressure. The residue was suspended in 30 mL of EtOAc andfiltered through a pad of celite. The filter cake was rinsed with 50 mLof EtOAc. The filtrate was poured into 30 mL of water and extracted with3×20 mL EtOAc. The combined organics were rinsed with 10 mL of brine,dried with MgSO₄, filtered, and concentrated to dryness. Purificationwas achieved by chromatography on silica using 20-55% EtOAc/hexane toafford 1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazin-5-ol as asolid (268 mg, 62%). LCMS ESI (+) (M+H) m/z 205/207/209.

Step D: Preparation of1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazin-5-one

A solution of 1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazin-5-ol(268.0 mg, 1.31 mmol) in dichloromethane (13 mL) at 25° C. was treatedwith Dess-Martin periodinane (720.7 mg, 1.70 mmol). After stirring foranother 30 min, the reaction was quenched by the addition of 10 mL ofsaturated Na₂S₂O₃ solution and 10 mL of saturated NaHCO₃ solution. Theresulting biphase stirred for 10 min. The reaction mixture was pouredinto 10 mL of water and extracted with 3×20 mL CH₂Cl₂. The combinedorganics were rinsed with 10 mL of brine, dried with MgSO₄, filtered,and concentrated to dryness. The product was used without furtherpurification. LCMS ESI (+) (M+H) m/z 203/205/207.

Step E: Preparation of1,4-diiodo-6,7-dihydro-5H-cyclopenta[d]pyridazin-5-one

A solution of 1,4-dichloro-6,7-dihydrocyclopenta[d]pyridazin-5-one (31.0mg, 0.15 mmol) in acetone (1.0 mL) was treated with sodium iodide (57.2mg, 0.38 mmol) and heated by microwave irradiation to 120° C. over 1.5h. Volatiles were removed by concentration under reduced pressure. Thereaction mixture was poured into 20 mL of water and extracted with 3×10mL EtOAc. The combined organics were rinsed with 10 mL of brine, driedwith MgSO₄, filtered, and concentrated to dryness. Purification wasachieved by chromatography on silica using 15-45% EtOAc/hexanes toafford 1,4-diiodo-6,7-dihydro-5H-cyclopenta[d]pyridazin-5-one as ayellow solid (32.7 mg, 55%). LCMS ESI (+) (M+H) m/z 387.

Step F: Preparation of1,4-diiodo-6,7-dihydrospiro[cyclopenta[d]pyridazine-5,2′-[1,3]dioxolane]

Trimethylsilyl trifluoromethanesulfonate (3.7 μL, 0.020 mmol) was addedto a solution of 1,4-diiodo-6,7-dihydrocyclopenta[d]pyridazin-5-one(15.6 mg, 0.040 mmol) and trimethyl(2-trimethylsilyloxyethoxy)silane(39.7 μL, 0.16 mmol) in dichloromethane (0.8 mL) cooled in an ice bath.The ice bath was removed and the reaction stirred at ambient temperatureovernight. The reaction mixture was quenched by adding triethylamine(22.5 μL, 0.16 mmol), stirring for 10 min, and then concentrating. Theresidue was dissolved in a mixture of 10 mL of CH₂Cl₂ and 10 mL waterand the layers separated. The aqueous layer was extracted further (2×10mL of CH₂Cl₂), the combined organics washed with brine (1×10 mL), driedover MgSO₄, filtered, and concentrated to dryness. NMR indicates thedesired product in reasonable purity. Used without further purification.LCMS ESI (+) (M+H) m/z 431.

Step G: Preparation of3-fluoro-5-((4-iodo-6,7-dihydrospiro[cyclopenta[d]pyridazine-5,2′-[1,3]dioxolan]-1-yl)oxy)benzonitrile

A solution of1′,4′-diiodospiro[1,3-dioxolane-2,5′-6,7-dihydrocyclopenta[d]pyridazine](11.0 mg, 0.026 mmol) and 3-fluoro-5-hydroxy-benzonitrile (3.5 mg, 0.026mmol) in DMF (0.5 mL) was treated with cesium bicarbonate (7.4 mg, 0.038mmol) and stirred at 90° C. overnight. The reaction mixture was pouredinto 20 mL of water and extracted with 3×10 mL TBME. The combinedorganics were rinsed with 10 mL of brine, dried with MgSO₄, filtered,and concentrated to dryness. Purification was achieved by chromatographyon silica using 15-40% EtOAc/hexane to afford3-fluoro-5-((4-iodo-6,7-dihydrospiro[cyclopenta[d]pyridazine-5,2′-[1,3]dioxolan]-1-yl)oxy)benzonitrileas a white solid (6.0 mg, 53%). LCMS ESI (+) (M+H) m/z 440.

Step H: Preparation of3-fluoro-5-((4-(trifluoromethyl)-6,7-dihydrospiro[cyclopenta[d]pyridazine-5,2′-[1,3]dioxolan]-1-yl)oxy)benzonitrile

A solution of3-fluoro-5-(4′-iodospiro[1,3-dioxolane-2,5′-6,7-dihydrocyclopenta[d]pyridazine]-1′-yl)oxy-benzonitrile(6.0 mg, 0.014 mmol) in DMF (0.6 mL) was sparged with nitrogen for 3minutes. The reaction mixture was treated sequentially with copper (2.6mg, 0.041 mmol) and sulfonium diphenyl(trifluoromethyl)-,1,1,1-trifluoromethanesulfonate (1:1) (11 mg, 0.027 mmol) undercontinuous nitrogen stream. The vessel was sealed and heated to 60° C.overnight. The reaction mixture was poured into 20 mL of water andextracted with 3×10 mL TBME. The combined organics were rinsed with 10mL of brine, dried with MgSO₄, filtered, and concentrated to dryness.Purification was achieved by chromatography on silica using 15-45%EtOAc/hexane to afford3-fluoro-5-((4-(trifluoromethyl)-6,7-dihydrospiro[cyclopenta[d]pyridazine-5,2′-[1,3]dioxolan]-1-yl)oxy)benzonitrileas a thin film (4.9 mg, 94%). LCMS ESI (+) (M+H) m/z 382.

Step I: Preparation of3-fluoro-5-((5-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)oxy)benzonitrile(Compound 42)

A solution of3-fluoro-5-[1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[d]pyridazine]-4′-yl]oxy-benzonitrile(4.9 mg, 0.013 mmol) in dichloromethane (1.0 mL) at 0° C. was treatedwith 70% aqueous perchloric acid (200 μL) and stirred at 25° C. for 2 h.The reaction mixture was cooled to 0° C., carefully quenched with amixture of 2 mL of saturated NaHCO₃/4 mL of water, and extracted with3×10 mL CH₂Cl₂. The combined organics were rinsed with 10 mL of brine,dried with MgSO₄, filtered, and concentrated to dryness. The product wasused immediately without further purification by dissolving in 1 mL ofMeOH, cooling to 0° C., and treating with sodium borohydride (0.5 mg,0.013 mmol). The reaction stirred for 15 minutes and was then quenchedby the addition of 0.5 mL of saturated NH₄Cl. Volatiles were removed byconcentration under reduced pressure. The reaction mixture was pouredinto 20 mL of water and extracted with 3×10 mL EtOAc. The combinedorganics were rinsed with 10 mL of brine, dried with MgSO₄, filtered,and concentrated to dryness. Purification was achieved by chromatographyon silica using 20-50%/o EtOAc/hexane to afford3-fluoro-5-((5-hydroxy-4-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)oxy)benzonitrileas a thin film (3.3 mg, 76%). Retention time HPLC (14 min)=4.76 minutes;LCMS ESI (+) (M+H) m/z 340; ¹H NMR (400 MHz, CDCl₃): δ 7.43-7.41 (m,1H), 7.33 (dt, 1H), 7.33-7.29 (m, 1H), 5.67-5.62 (m, 1H), 3.36-3.26 (m,1H), 3.05 (ddd, 1H), 2.63-2.53 (m, 1H), 2.40-2.30 (m, 2H).

Example 11: Synthesis ofN-(3-Chlorophenyl-4,6-t2)-4-nitrobenzo[c][1,2,5]oxadiazol-5-amine

Step A: Synthesis of 3-chlorobenzen-4,6-t₂-amine

3-Chloro-4,6-diiodoaniline (100 mg,) was dissolved in methanol (3 mL)and added with triethylamine (0.1 mL) and submitted for overnighttritiation using 50 Ci of tritium gas, at room temperature. Labiletritium was removed by dissolving the crude reaction mixture in methanol(3 mL) and bringing to dryness under vacuum. Labile removal was done induplicate. The crude tritiated material was purified by preparative TLC(Silica gel, 1000μ) using hexane:ethyl acetate:AcOH (85:14:1). Theproduct band was eluted with ethyl acetate to give3-chlorobenzen-4,6-t₂-amine (yield=600 mCi, radiochemical purity was>98%).

Step B: Synthesis ofN-(3-Chlorophenyl-4,6-t2)-4-nitrobenzo[c][1,2,5]oxadiazol-5-amine

A stirred mixture of 5-chloro-4-nitro-2,1,3-benzoxadiazole (20 mg, 0.1mmol), 3-chlorobenzen-4,6-t₂-amine (600 mCi) and Cs₂CO₃ (65 mg, 0.20mmol) in DMF (1 mL) was heated at 60° C. for 1h. After cooling, thereaction mixture was partitioned between EtOAc and water. The aqueouslayer was extracted with EtOAc. The combined organic layers were washedwith water and brine, dried and concentrated. The residue was purifiedby preparative HPLC on an ACE-5 C18 Semi-prep column, 250×10 mm, 100 Å.Elution was carried out isocratically using 0.1% TFA inwater/Acetonitrile (35:65) to give the title compound (478 mCi, 80%).

Example 12: HIF-2α Scintillation Proximity Assay (SPA)

The total assay volume was about 100 μL in the following configuration:2 μL compound in 100% DMSO, 88 μL buffer with protein and probe and 10μL of SPA beads. The compound was diluted in a master plate consistingof a 10-point dose response with a 3-fold compound dilution from 100 μMto 5 nM. Assays were run on a 96-well plate in which one column,designated as the high signal control, contained DMSO with no compoundand another column, designated as the low signal control, contained noprotein. Prior to plating out of compound, a buffer solution, consistingof 25 mM TRIS pH 7.5 (Sigma), 150 mM NaCl (Sigma), 15% Glycerol (Sigma),0.15% BSA (Sigma), 0.001% Tween-20 (Sigma), 150 nMN-(3-Chlorophenyl-4,6-t₂)-4-nitrobenzo[c][1,2,5]oxadiazol-5-amine and100 nM HIF-2α HIS TAG-PASB Domain, was made and allowed to equilibratefor 30 minutes. Compounds that were to be tested were then plated in toa 96-well white clear bottom Isoplate-96 SPA plate (Perkin Elmer). Tothe compounds was added 88 μL of the buffer solution, then the platecovered with a plastic cover and aluminum foil, placed onto a shaker andequilibrated for 1 hour. After equilibration, 10 μL of a 2 mg/mLsolution of YSi Cu His tagged SPA beads (Perkin Elmer) were then addedto each well of the plate, covered and equilibrated for another 2 hours.The plates were then removed from the shaker, placed into a 1450 LSC andluminescence counter MicroBeta Trilux (Perkin Elmer) to measure theextent of probe displacement. The percent inhibition was determined andIC₅₀ values were calculated using the Dotmatics system based on thefollowing equation: % inhibition=[(high control−sample)/(highcontrol−low control)]×100.

Example 13: VEGF ELISA Assay

About 7500 786-O cells in 180 μL of growth medium were seeded into eachwell of a 96-well, white, clear bottom plate (07-200-566, FisherScientific) on day one in the following layout:

Four hours later, serial dilutions of 10× compound stocks were made ingrowth medium from 500×DMSO stocks, and 20 μL of those 10× stocks wereadded to each well to make final concentrations as follows (μM): 20,6.67, 2.22, 0.74, 0.25, 0.082, 0.027, 0.009, 0.003, 0.001, and 0. Eachconcentration was plated in duplicate. About 20 hours later, medium wasremoved by suction and each well was supplied with 180 μL of growthmedium. About 20 μl freshly-made 10× compound stocks were added to eachwell. About 24 hours later, cell culture medium was removed and the VEGFconcentration determined using an ELISA kit purchased from R&D systems,following the manufacturer's suggested method. The EC₅₀ was calculatedby GraphPad Prism using the dose-response-inhibition (four parameter)equation. The cell-seeded plate was then subjected to CellTiter-Gloluminescence cell viability assay (Promega) by adding 50 μL of CelltiterGlo reagent into each well and shaking the plate for 8 minutes at 550rpm (Thermomixer R, Eppendorf) then the luminescence signal immediatelyread in a plate reader (3 second delay, 0.5 second/well integrationtime, Synergy 2 multi Detection Microplate reader).

Example 14: Luciferase Assay

786-O-Hif-Luc single clone cells were obtained by infecting 786-O cells(ATCC® CRL-1932™) with commercial lentivirus that delivers a luciferasegene driven by multiple HIF responsive elements (Cignal Lenti HIFReporter (luc): CLS-007L, Qiagen) at Multiplicity of Infection (MOI) of25 for 24 hours. The cells were replenished with fresh medium(Dulbecco's Modified Eagle's Medium (DMEM, D5796, Sigma) supplementedwith 10% FBS (F6178, Sigma), 100 units penicillin and 100 μgstreptomycin/mL (P4333, Sigma)) for another 24 hours. A pool of infectedcells were then selected against 2 μg/mL of puromycin (P8833, Sigma) for10 days followed by limited dilution to select single clones. The cloneswere tested for their response to HIF-2 inhibitors and the ones thatshowed the biggest dynamic range (786-0-Hif-Luc) were expanded and usedfor the luciferase assay. For the luciferase assay, about 7500786-O-Hif-Luc cells in 90 μL growth medium were seeded into each well ofa 96-well white opaque plate (08-771-26, Fisher scientific) a day beforetreatment with the layout:

On treatment day, serial dilutions of 10× compound stocks were made ingrowth medium from 500×DMSO stocks, and 10 μL of the 10× stocks wereadded to each well to make final concentrations as follows (μM): 20,6.67, 2.22, 0.74, 0.25, 0.08, 0.027, 0.009, 0.003, 0.001, and 0. Eachconcentration was tested in triplicate. After about 24 hours, luciferaseactivity was determined using ONE-Glo Luciferase Assay Reagent (E6110,Promega) following the manufacturer's recommended procedure. EC₅₀ werecalculated using Dotmatics software.

Table 2 shows biological activities of selected compounds in Luciferase,VEGF ELISA and Scintillation Proximity assays. Compound numberscorrespond to the numbers and structures provided in Table 1 andExamples 1-10.

TABLE 2 Less than 50 nM to 250 nM to Greater than 50 nM (++++) 249 nM(+++) 1000 nM (++) 1000 nM (+) Scintillation 1, 2, 3, 8, 9, 14, 20, 4,13, 17, 24, 27 7, 12, 21, 25, 36 5, 6, 10, 11, 16, 18, Proximity 22, 23,34, 37, 40 19, 26, 28, 29, 30, Assay 31, 32, 33, 35, 38, IC₅₀ (nM) 39,42 Mean 1, 14, 22, 37 3, 34 9 VEGF ELISA EC₅₀ (nM) Mean 1, 3, 14, 22,37, 40 9, 13, 23, 27, 34 2, 4, 7, 8 6, 10, 12, 17, 20, Luciferase 21, 42EC₅₀ (nM)

Example 15: In Vivo Efficacy Studies

PK/PD studies for Compounds 22, 34 and 37: All compounds were formulatedwith 10% absolute ethanol, 30% PEG400, 60% water containing 0.5%methylcellulose and 0.5% Tween80®. About 5×10⁶ 786-0 renal cellcarcinoma cells (ATCC® CRL-1932™) in PBS and Matrigel (1:1 in volume)were inoculated subcutaneously in the right flanks of 16 SCID/Biege miceat 6-7 weeks of age for tumor xenograft development. When the xenograftsreached about 750 mm³ in size, the tumor bearing mice were randomlygrouped into four groups (n=3). The animals were treated with eithervehicle or test compound (Compound 22, Compound 34 or Compound 37) as asingle agent at 10 mg/kg by oral gavage for six doses in total at a 12hour dosing interval. All animals were sacrificed at 12 hours post lastdose. Tumors and plasma were collected from each animal. Total RNA wasextracted from the tumors, and the expression levels of putative HIF-2αregulated genes were determined by qRT-PCR. HIF-2α target genes VEGF,PAI-1 and CCND1 displayed a significant reduction in response tocompound treatment as depicted in FIG. 1. The level of human VEGFA wasasssessed using an ELISA assay. As shown in FIG. 2, compound treatmentled to a significant reduction in human VEGFA in the plasma, reflectingthe inhibition of HIF-2α in the 786-O tumor xenografts.

1. A compound of Formula I-C:

or a pharmaceutically acceptable salt or prodrug thereof, wherein: X isCR⁵ or N; Y is CR⁶ or N, wherein at least one of X and Y is N; Z is —O—,—S—, —S(O)—, —S(O)₂—, —C(O)—, —C(HR⁷)—, —N(R⁸)—, C₁-C₃ alkylene, C₁-C₃heteroalkylene, C₁-C₃ alkenylene or absent; R¹ is alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl; R⁴ is nitro, halo,cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl,sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; R⁵, R⁶, R⁷ and R⁸ areindependently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; R¹¹ ishydrogen, halo, hydroxy, alkoxy or amino; R¹² is hydrogen, alkyl,alkenyl or alkynyl; or R¹¹ and R¹² in combination form ═O, ═CH₂ or═N(OH); each of R¹³ is independently selected from the group consistingof hydrogen, fluoro, chloro, hydroxy, alkyl and heteroalkyl; and twoR¹³s and the carbon atom(s) to which they are attached may form a 3- to8-membered cycloalkyl or heterocycloalkyl moiety; and n is 0, 1, 2, 3 or4.
 2. (canceled)
 3. The compound of claim 1, wherein R¹² i hydrogen, R¹³is fluoro and n is 1, 2, or
 3. 4. The compound of claim 1, representedby a formula selected from:


5. The compound of claim 1, wherein R¹ is monocyclic cycloalkyl,monocyclic aryl, monocyclic heteroaryl or bicyclic heteroaryl.
 6. Thecompound of claim 5, wherein R¹ is cyclobutyl, phenyl or pyridyl. 7.(canceled)
 8. (canceled)
 9. The compound of claim 1, wherein R¹ issubstituted with at least one substituent selected from the groupconsisting of halo, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano. 10.The compound of claim 9, wherein R¹ is substituted with one to sixfluorines.
 11. The compound of claim 6, wherein R¹ is selected from:


12. The compound of claim 1, wherein R⁴ is cyano, fluoroalkyl, sulfinyl,sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. 13.(canceled)
 14. The compound of claim 1, wherein R¹¹ is hydroxy or amino.15-17. (canceled)
 18. The compound of claim 1, wherein Z is —O—.
 19. Thecompound of claim 1, wherein: R⁴ is fluoroalkyl or sulfonyl; n is 0, 1,2 or 3; Z is —O—; R¹¹ is hydroxy; and R¹² is hydrogen. 20-22. (canceled)23. The compound of claim 19, wherein R¹ i monocyclic aryl, monocyclicheteroaryl, bicyclic heteroaryl, monocyclic cycloalkyl, orheterocycloalkyl.
 24. (canceled)
 25. The compound of claim 23, whereinR¹ is substituted with at least one substituent selected from the groupconsisting of halo, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano. 26.The compound of claim 1, wherein X is N and Y is CR⁶.
 27. (canceled) 28.(canceled)
 29. A compound selected from the group consisting of:


30. A pharmaceutical composition comprising the compound of claim 1 anda pharmaceutically acceptable carrier.
 31. A method of inhibiting HIF-2αsignaling output, comprising contacting HIF-2α with an effective amountof the compound of claim
 1. 32-37. (canceled)
 38. A method of treating acondition associated with HIF-2α, comprising administering to a subjectin need thereof an effective amount of the compound of claim
 1. 39. Amethod of treating von Hippel-Lindau (VHL) disease, comprisingadministering to a subject in need thereof an effective amount of thecompound of claim
 1. 40. (canceled)
 41. A method of treating renal cellcarcinoma, comprising administering to a subject in need thereof atherapeutically effective amount of the compound of claim
 1. 42.(canceled)
 43. The method of claim 41, wherein said renal cell carcinomais clear cell renal cell carcinoma (ccRCC).
 44. (canceled)